中文   |   English   |   Email Alert
Fig/Tab
Advanced Search
image

Surface-Enhanced Raman Spectroscopy on Detection of Myocardial Injury-Related Biomarkers

Qian Peng , Jingjing Zhang , Xinyue Fang , Jie Ni , Chunyuan Song

Progress in Chemistry ›› 2022, Vol. 34 ›› Issue (12) : 2573 -2587.

PDF
Progress in Chemistry ›› 2022, Vol. 34 ›› Issue (12) : 2573-2587 DOI: 10.7536/PC220602
research-article
Scan to read & Share
Surface-Enhanced Raman Spectroscopy on Detection of Myocardial Injury-Related Biomarkers
Author information +
History +
PDF

Abstract

Cardiovascular disease (CVD) is the leading cause of death worldwide, while acute myocardial infarction (AMI) is the main cause of cardiovascular death. Early and rapid diagnosis of AMI is essential to reduce mortality in patients with CVD. Due to the lack of sufficient sensitivity of common detection methods such as electrocardiogram (ECG), screening for AMI-related biomarkers and conducting sensitive detection has become an important tool for early and accurate detection of AMI. Currently, cardiac troponin I (cTnI), creatine kinase-MB isoenzymes (CK-MB) and myoglobin (Myo) are identified as important biomarkers of myocardial injury. In the past few decades, many biosensors have been developed to detect biomarkers of myocardial injury, among which surface-enhanced Raman spectroscopy (SERS)-based detections have developed rapidly and showed unique advantages and broad application prospects. In this paper, several biomarkers of myocardial injury and their associations with AMI are introduced firstly, and the principles, advantages and limitations of the conventional detection methods for AMI-related biomarkers detection are outlined. Based on this, the research progress of SERS on detection of biomarkers of myocardial injury in recent years is reviewed, and the application and prospect of SERS in AMI diagnosis and the problems and direction of further study are discussed.

Contents

1 Introduction

2 Cardiac biomarkers

2.1 Cardiac troponin

2.2 Creatine kinase-MB isoenzymes

2.3 Myoglobin

3 Conventional detection methods

3.1 ELISA

3.2 Electrochemical immunoassay

3.3 Chemiluminescence immunoassay

3.4 Fluorescence immunoassay

4 SERS detection of biomarkers of myocardial injury

4.1 SERS and SERS-based biosensing

4.2 SERS detection of myocardial injury-related biomarkers

5 Conclusion and outlook

Graphical abstract

Keywords

cardiovascular disease (CVD) / acute myocardial infarction (AMI) / myocardial biomarkers / surface-enhanced Raman spectroscopy (SERS) / biosensor

Cite this article

Download citation ▾
Qian Peng, Jingjing Zhang, Xinyue Fang, Jie Ni, Chunyuan Song. Surface-Enhanced Raman Spectroscopy on Detection of Myocardial Injury-Related Biomarkers. Progress in Chemistry, 2022, 34(12): 2573-2587 DOI:10.7536/PC220602

登录浏览全文

4963

注册一个新账户 忘记密码

1 Introduction

Cardiovascular disease (CVD) is the leading cause of death worldwide. According to the World Health Organization (WHO), CVD will cause more than 23.3 million deaths annually by 2030[1]. CVD mainly includes heart and vascular diseases, most of which are related to atherosclerosis. The plaque that accumulates in the arteries can restrict blood flow, which can lead to atherosclerosis[2]. Acute myocardial infarction (AMI) is one of the clinical forms of CVD, which is defined as myocardial necrosis (cell death) due to long-term ischemia and reduced blood supply to the heart. It is an irreversible myocardial injury caused by hypoxia and is the main cause of death from cardiovascular disease[3,4]. Morbidity and mortality are significantly higher in patients due to reduced blood flow to the heart[5]. Usually, patients with AMI suffer from chest pain, weakness, sweating, nausea, vomiting, and sometimes loss of consciousness. However, these symptoms may be misdiagnosed as gastrointestinal or pulmonary diseases due to their atypical clinical manifestations, which can not be treated in time or even endanger their lives[6][7]. Therefore, early diagnosis is essential for effective treatment of patients with AMI. Before the development of myocardial biomarker detection techniques, AMI was mainly diagnosed by electrocardiogram (ECG) in patients with acute chest pain. ECG is a commonly used method to measure and diagnose abnormal cardiac rhythm, which can be used to diagnose the damage of conductive tissue carrying electrical signals, but it lacks sensitivity and can not detect all myocardial damage[8]. The main limitation of ECG is that it can only represent the cardiac activity at a certain moment, and the patient may even show a normal or non-diagnostic ECG when he is in the emergency room, so it usually needs to be tested many times according to the changes of the patient's clinical condition[9,10]. In addition, waveform recognition is used in ECG evaluation to compare with expected normal results, but the interpretation of the final results by the physician who reads the ECG is subjective[11]; Moreover, the electrocardiogram has no significant fluctuation in patients with non-ST-segment elevation myocardial infarction (NSTEMI). According to the survey, 25% of AMI patients have no obvious symptoms such as chest, back or chin pain[12]. In conclusion, although ECG can be used to identify cardiovascular diseases such as myocardial ischemia, myocardial infarction, conduction defects, and arrhythmias, it is not reliable in the diagnosis of AMI[13]. In order to overcome the limitations of ECG and the problems in the diagnosis of AMI, the use of myocardial biomarkers to assist ECG detection has attracted more and more attention from clinicians, and has become an important means of AMI diagnosis (Figure 1)[14]. Combining suboptimal sensitivity ECG with myocardial biomarker detection is an effective way to identify AMI[15].
Cardiac troponin I (cTnI), creatine kinase isoenzyme (CK-MB), and myoglobin (Myo) are currently recognized as specific biomarkers for the diagnosis of AMI. Enzyme-linked immunosorbent assay, chemiluminescence, fluorescence and electrochemical immunoassay have been developed to specifically detect a variety of myocardial biomarkers, but these detection methods have some problems, such as single detection index, insufficient sensitivity, poor accuracy, long detection time and enzyme catalysis. Therefore, surface-enhanced Raman spectroscopy (SERS), which has the advantages of high sensitivity and multiple detection, has shown great potential in the detection of AMI.
This article first introduces a variety of myocardial biomarkers and their association with AMI, and then summarizes the principles, advantages and limitations of the main myocardial biomarker detection methods.This paper focuses on the emerging surface-enhanced Raman spectroscopy and its latest research progress in myocardial biomarker sensing, and discusses the application prospects of this technology in AMI diagnosis and the bottlenecks to be broken through.

2 Myocardial biomarker

A biomarker is a signal indicator of a certain abnormal change occurring in an organism at different biological levels (molecular, cellular, individual, etc.), which can indicate the pathogenic process caused by a disease. For example, any small change in a disease-related biomarker measured in the blood can relatively correctly and quickly predict the ongoing related disease[14,16]. Myocardial biomarkers are biomarkers that are highly expressed in myocardial tissues but not in non-cardiac tissues. They have been widely used in basic research and clinical diagnosis. They are an important part of the diagnostic criteria for AMI and an important indicator for clinical detection of AMI[4,17]. The ideal myocardial biomarker is released rapidly and linearly after AMI, exists in the circulation for a long time, and is highly sensitive and specific for AMI. Accurate detection of AMI can be achieved by identifying protein markers of myocardial injury present in the blood that are released as a result of myocardial cell damage[18]. Protein markers used to detect AMI in the early stage include aspartate aminotransferase, total lactate dehydrogenase and lactate dehydrogenase isoenzyme, which are widely distributed in cardiac tissue and cannot show high specificity for AMI, so these biomarkers are not suitable for accurate assessment of AMI[19][20]. In 2000, the European Society of Cardiology and the American College of Cardiology (ESC/ACC) announced new indications for the diagnosis of AMI, and provided the next generation of myocardial biomarkers for the identification of AMI: cardiac troponin T and I (cTnT and cTnI), creatine kinase (CK), myoglobin (Myo), and heart-type fatty acid-binding protein (H-FABP)[21]. For example, in the clinical setting of acute ischemia, AMI is diagnosed when blood levels of sensitive and specific proteins, such as cardiac troponin and creatine kinase isoenzyme (CK-MB), are elevated.

2.1 Cardiac troponin

In recent years, cardiac troponin is the preferred biomarker of myocardial injury for clinical diagnosis of AMI.Cardiac troponin is normally produced only in the myocardium and can show near absolute myocardial tissue specificity and high clinical sensitivity to myocardial ischemia, even presenting microscopic areas of myocardial necrosis[22,23]. There are two kinds of cardiac troponins, cardiac troponin T (cTnT) and cardiac troponin I (cTnI). Studies have shown that both cardiac troponins are closely related to CVD death, with cTnI showing a higher association with AMI[24]. Therefore, cTnI is considered to be the gold standard for the diagnosis of AMI and a class I indication for the diagnosis of AMI.
The cardiac isoform of human cTnI consists of 209 amino acid residues with a molecular mass of ∼ 22.5 kDa[25,26]. Troponin has been widely used as a biomarker to detect myocardial ischemia since Cummins et al developed a radioimmunoassay for cTnI in 1987[27]. The isoform of cTnI in cardiac muscle is different from that in skeletal muscle. This difference allows researchers to develop highly specific antibodies against cTnI without cross-reacting with other isoforms of troponin[28]. Studies have shown that a cTnI concentration of 0.5 to 2.0 ng/mL is considered to be the dividing line between normal people and patients[29]. Under normal circumstances, the cTnI in the blood of healthy people is low (< 0.06 ng/mL), but after AMI, the cTnI can quickly enter the blood, and the concentration can rise to 50 ng/mL within 4 to 6 hours, and finally reach the level of about 550 ng/mL. The highest concentration generally occurs 12 to 24 hours after AMI, and can increase to 5 to 12 times the normal level and last for several days[6,30,31]. The abnormally high concentration of cTnI will remain for 6 to 8 days before returning to its standard state, so it can be diagnosed as AMI for a long time.

2.2 Creatine kinase isoenzyme

Another myocardial biomarker that can identify AMI is creatine kinase MB (CK-MB), an isoenzyme of creatine kinase, which is most abundant in the heart[32]. However, it accounts for 1% to 3% of skeletal muscle creatine kinase and is present in small amounts in other organs, such as the small intestine, uterus, prostate, and diaphragm, so its specificity is low[33]. The concentration of CK-MB in serum increased after 4 to 6 H, reached the peak at 12 to 24 H, and returned to the baseline value at 3 to 4 d[34]. However, its activity is affected by multiple analytical variables, such as detection temperature and pH[35,36]. Several studies have confirmed that although CK-MB has lower tissue specificity than cTnI, its good sensitivity makes it advantageous in recording clinical data of AMI[37⇓~39].

2.3 Myoglobin

After AMI, myoglobin (Myo) is released into the blood along with cTnI and CK-MB[40]. Myo is a small (17.8 kD) globular hemoprotein present in cardiac myocytes and skeletal muscle[41]. Because of its small size, it will be released into the blood within 1 to 3 hours after AMI and reach its maximum concentration within 6 to 12 hours, while cTnI and CK-MB are released after 4 to 6 hours after AMI[40,42]. In addition, unlike cTnI and CK-MB, the concentration of Myo can rapidly increase from 90 pg/mL to more than 250 ng/mL when the concentrations of CK-MB and troponin are still at normal levels, and the concentration in the blood can be increased up to 600 ng/mL compared with the normal expression range (i.e., 100-200 ng/mL)[43]. However, like CK-MB, it lacks specificity for cardiac tissue due to the presence of large amounts of Myo in skeletal muscle. Therefore, neither a single Myo nor CK-MB expression level is suitable to be used as a criterion for an accurate diagnosis of AMI, but rather needs to be used in combination with other myocardial biomarkers[44]. Therefore, the development of cost-effective, accurate and timely sensors that simultaneously detect multiple myocardial biomarkers for the diagnosis, monitoring, and prognosis of AMI is essential.

3 Common detection methods and sensors for myocardial biomarkers

Myocardial biomarker sensors are integrated diagnostic devices that combine biological or bio-derived sensing elements with physicochemical sensors, which can be used to detect and quantify myocardial biomarkers[45,46]. Generally, the transducer surface of a suitable biomarker sensor is immobilized with a biological recognition molecule (such as DNA, RNA or antibody, etc.), and based on a specific detection method, the biochemical signal is converted into a quantifiable photoelectric signal by electricity, optics, mass change (piezoelectric/acoustic wave), magnetic force, etc[47][48,49][50,51][52][53]. Compared with traditional technologies such as ECG, myocardial biomarker sensors have the advantages of high sensitivity, high selectivity and rapid analysis. At present, the main methods for the detection and quantification of different AMI protein markers include enzyme-linked immunosorbent assay (ELISA), chemiluminescence immunoassay (CLIA), fluorescence immunoassay (FIA), electrochemical immunoassay and so on.

3.1 Enzyme-linked immunosorbent assay

The principle of enzyme-linked immunosorbent assay is to use antibody and enzyme-mediated color change to detect whether there is target antigen (protein, peptide, hormone, etc.) or antibody in the sample. The most commonly used enzymes are horseradish peroxidase and alkaline phosphatase, and o-phenylenediamine is usually used as the chromogenic substrate. The basic principle is shown in Figure 2 (A).That is to say, the capture antibody fixed or adhered to the surface of the plate hole is combined with the antigen to be detected, and the detection antibody, the antigen and the capture antibody form a sandwich structure.After the enzyme-conjugated secondary antibody is combined with the detection antibody, the antigen is detected by qualitatively measuring the color change or fluorescence of the chromogenic substrate of the enzyme, and the antigen itself can also be directly or indirectly detected[54][55]. For example, Juronen et al. Developed a rapid ELISA method for quantifying Myo in serum using o-phenylenediamine as a substrate[56].
Although ELISA has the advantages of simple operation, high cost-effectiveness and high sensitivity in the diagnosis of AMI, the enzyme-mediated color change will continue indefinitely, on the one hand, with the extension of time, the color intensity will not be able to accurately reflect the detection results and lead to false positive[57]; On the other hand, because the antibody or antigen is directly immobilized on the surface of the well, their non-specific binding to the plate can also lead to false positive results[58,59]. This sandwich assay, ELISA, usually involves a series of peptide binding and washing steps, resulting in time-consuming and labor-intensive defects, which are inconsistent with the need for rapid assays for the treatment of cardiac patients, thus requiring the development of more sensitive and convenient assays.

3.2 Electrochemical immunoassay

Electrochemical immunoassay is a method for quantifying the concentration of antigen/antibody based on electrochemical signals and biospecific recognition reactions. As shown in fig. 2 (B), specific antibody molecules are modified on the surface of the electrode. When the antibody immobilized on the surface of the electrode captures the antigen, charge exchange occurs between the molecules, resulting in changes in the local current or voltage on the electrode surface, and the immunodetection of the antigen is achieved through the electrochemical signal of this specific reaction[60,61]. Based on this working principle, electrochemical sensors can convert chemical information into measurable electrical signals. For example, Ren and Wu et al. Used the electrochemical signal of the complex of covalent organic framework with gold nanoparticles and electron mediator toluidine blue to quantitatively detect cTnI[62].
Electrochemical immunosensing has the advantages of good selectivity, simple equipment and short response time, but its detection limit is not enough for ultrasensitive detection[63,64][65]. Although it provides a large amount of quantitative information about the target, electrochemical immunosensing still lacks chemical specificity, that is, the exact chemical characteristics of the analyte are difficult to distinguish, and optical detection is often required to provide supplementary information for specific recognition of the analyte[66]. In addition, myocardial biomarkers are easily detached from the substrate in electrolyte solutions, and the chemical properties of signaling molecules may be changed by redox reaction processes, which can affect the results[67].

3.3 Chemiluminescent immunoassay

Chemiluminescence (CL) is a detection method based on the luminescence of chemical reactions, which is based on the principle that excited molecules emit light when they relax to their ground state. As shown in fig. 2 (C), chemiluminescence immunoassay (CLIA) combines a highly sensitive chemiluminescence assay technique with a highly specific immunoassay, and is a method for determining the concentration of a sample according to the intensity of light emitted by a chemical reaction, in which the luminescence signal comes from a chemical reaction converted from an immune reaction between an antibody (Ab) and an antigen[60][68]. Chemiluminescent (CL) substrates are generally luminol, isoluminol and its derivatives, acridine esters and their derivatives, etc. The most commonly used protein labeling enzymes in CLIA are horseradish peroxidase (HRP) and alkaline phosphatase (ALP)[69]. For example, Paek et al. Used HRP enzyme tracer and substrate luminol to produce CL signal, and developed CL biosensor for real-time detection of cTnI[70].
CLIA has been widely used in clinical AMI detection because of its advantages of no light source and wide dynamic detection range. However, CLIA still has some shortcomings in practical application, such as non-specific adsorption of complex samples and substrates, lack of stability of substrates and protein labeling enzymes, and limited accuracy, which may affect the detection results and delay the timely rescue of patients[71,72][73,74].

3.4 Fluorescence immunoassay

Fluorescence immunoassay (FIA) is one of the classifications of optical biosensors. As shown in fig. 2 (D), in the fluorescence-based detection, the detection antibody is labeled with a fluorescent tag (such as fluorescein isothiocyanate, rhodamine, coumarin, cyanine, etc.), and after the capture antibody is bound to the target antigen,The detection antibody with a fluorescent tag specifically binds to the antigen to form a "sandwich" structure, and the fluorescence intensity indicates the presence of the target antigen and the strength of the interaction between the target antigen and the detection antibody[75][76]. For example, Yoon et al. Reported the immunodetection of cTnI based on fluorescent microspheres[77].
The nondestructive, highly sensitive, and easily labeled ability of FIA makes it a preferred method for AMI detection[78,79]. Nevertheless, fluorescence methods still have some limitations, such as high cost, poor photostability, cumbersome labeling process and easy interference with the function of biomolecules, fluorescence photobleaching will also affect the stable detection of target biomarkers, and the relatively wide fluorescence peak is not conducive to multiple joint detection[80][81][82][75].

4 Myocardial biomarker detection method based on SERS

Surface-enhanced Raman spectroscopy (SERS) biosensing technology is an analytical technique for the detection of biological samples with high sensitivity and selectivity. Its main advantages are as follows: 1) Raman spectroscopy is a fingerprint spectrum of molecules, which can realize the label-free detection of biomolecules and uses materials with high biocompatibility[83][84]; 2) SERS detection only needs a trace amount of sample and has the capability of trace detection[85]; 3) the sensitivity is high, and the detection at the single molecule level can be realized[86,87]; 4) The SERS band is sharp, enabling simultaneous multiplex detection of multiple analytes using a single excitation wavelength[88]. In recent years, SERS biosensors have been used for the detection and Bioanalysis of various diseases, including various cancers, Alzheimer's disease and Parkinson's disease, and have become a powerful analytical tool, showing great application prospects in the field of biochemical detection[89⇓~91][92][93][94⇓~96]. This article will focus on the research and application progress of SERS biosensor in myocardial biomarker detection.

4.1 SERS and its biosensing technology

In 1974, Fleischmann et al. First observed the SERS phenomenon, that is, the pyridine monolayer adsorbed on a rough silver electrode showed unexpectedly high intensity Raman scattering under light irradiation[97]. Soon after, Jeanmaire and van Duyne and Albrecht and Creighton confirmed Fleishman's discovery, studied and proposed that this was a Raman enhancement effect caused by rough metal surfaces, and named it surface enhanced Raman scattering[98][99]. Previous studies have shown that the SERS enhancement effect comes from two aspects: physical enhancement and chemical enhancement. Physical enhancement is also called electromagnetic field enhancement. The light excited by localized surface plasmon resonance (LSPR) irradiates the metal surface to form a significantly enhanced electromagnetic field, which increases the intensity of Raman scattering produced by molecules adsorbed on the metal surface. This is the main source of SERS enhancement, and its enhancement factor can reach 1011[100][101]. Researchers generally consider the contribution of chemical enhancement to be much smaller than that of electromagnetic enhancement, with an enhancement factor of the order of 102~103[102]. The chemical enhancement mechanism is mainly related to the charge transfer mechanism, in which the Raman signal is significantly enhanced by the resonance between the excitation wavelength and the electronic state of the metal molecule due to the charge transfer between the metal surface and the Raman molecule[101].
In recent years, researchers have developed more and more SERS-based biosensing technologies for the detection and Bioanalysis of nucleic acids, proteins, small molecules and pathogens, among which SERS sensing technologies and sensors for the detection of myocardial biomarkers mainly using the "detection substrate-analyte-SERS probe" sandwich structure have been developed rapidly[103,104]. In the sandwich structure detection scheme, the detection substrate is constructed by modifying the surface of the substrate or the nanoparticle with biomolecules capable of specifically recognizing the analyte, and the SERS probe is prepared by modifying the surface of the SERS active nanoparticle with Raman reporter molecules and specific biomolecules, respectively. Rhodamine 6G (R6G), crystal violet, malachite green, 4-mercaptobenzoic acid (4MBA) and 5 '-dithiobis (2-nitrobenzoic acid) (DTNB), which have large Raman scattering cross sections and clear characteristic peaks, are usually selected as Raman reporters[105].
In SERS immunodetection technology, specific antibodies that can recognize and bind to the target analyte (antigen) are used to biofunctionalize the detection substrate (that is, to construct the immunodetection substrate), while SERS active nanoparticles are modified by Raman reporter molecules and antibodies to construct SERS immunoprobes. As shown in fig. 3 (A), in the detection process, the detection substrate immunologically recognizes and captures the analyte, then the SERS immune probe is bound to the detection substrate through immune binding with the analyte, and finally the SERS signal of the immune probe is used for the analysis of the target analyte[88]. In addition to the antigen-antibody immune recognition mechanism, the specific recognition based on aptamer and protein is also a new strategy for the construction of SERS sensors[106]. Aptamer is a single-stranded nucleic acid, also known as "chemical antibody", which can recognize heavy metal ions, nucleic acids, proteins, peptides, cells and microorganisms with high affinity and selectivity[107,108]. SERS sensors based on aptamer recognition mechanism have been used to detect small organic molecules, inorganic pollutants, proteins, and even at the cellular level[109][110][111][112]. In the aptamer-based SERS detection scheme, on the one hand, a high-performance aptamer capable of specifically binding to an analyte is immobilized on a substrate to construct a capture unit capable of specifically capturing the analyte; On the other hand, a SERS probe modified with both a Raman reporter molecule and an aptamer (SERS aptamer probe) is prepared and used as a signal output unit. Finally, the "detection substrate-analyte-SERS aptamer probe" sandwich structure complex formed after the detection of the analyte is used to output the SERS spectrum under laser excitation (as shown in Figure 3 (B)), so as to realize the qualitative and quantitative detection of the analyte[113,114]. In the SERS detection technology based on sandwich structure, the specificity of SERS sensor depends on the specific binding of antigen-antibody or the specific interaction between target and aptamer, while the sensitivity mainly depends on the sensitive signal output performance of SERS probe[115].

4.2 Detection of Myocardial Biomarkers Based on SERS

4.2.1 cTnI assay

In the past few decades, due to the high sensitivity and specificity of SERS, SERS technology has gained great attention in the detection of myocardial biomarker cTnI, and a series of SERS-based detection reagents and sensors have been developed. For example, Chen et al. Developed a SERS immunosensing system for cTnI detection using gold nanoparticles (AuNPs), graphene oxide (GO) and magnetic beads (MB)[116]. As shown in Fig. 4 (A), they used MB modified by monoclonal antibody as a capture probe, and used AuNPs-functionalized GO labeled by antibody and Raman molecules as a SERS immunoprobe. When cTnI was present, cTnI was captured through "antibody-antigen-antibody" interaction and a "capture probe-target analyte-SERS immunoprobe" sandwich complex was formed. Based on the excellent SERS enhancement ability of GO/AuNPs complex and the high immunobinding ability between cTnI and antibody-modified GO/AuNPs complex, this method successfully achieved highly sensitive detection of cTnI, with a good linear response in the range of 0. 01 ~ 1000 ng/mL and a low limit of detection (LOD) of 5 pg/mL. In order to further study the clinical application potential of SERS immunosensing technology, they added cTnI to serum at different concentrations and measured SERS. The results showed that the SERS immunosensor based on GO/AuNPs had the potential to diagnose AMI clinically. In addition, the detection technology of SERS combined with lateral flow immunoassay (LFIA) has also been developed for cTnI detection. Khlebtsov et al. Reported a cTnI detection strategy combining GAP-enhanced SERS probe and LFIA as shown in fig. 4 (B)[117]. They prepared a gold nanorod core-gold shell nanostructure with Raman molecules embedded in the core-shell gap (GERT), and modified anti-cTnI monoclonal antibody on the surface of the Au shell to prepare a SERS immunoprobe. On the LFIA chip, the detection liquid containing cTnI moved along the cellulose membrane and was captured in a specific area where the cTnI antibody was immobilized (i.e., the detection strip, T line), and further combined with the GERT SERS immunoprobe to form a sandwich structure at the T line. The excess detection liquid was adsorbed by the reference strip (C line), and finally the SERS spectrum was used to sensitively detect cTnL at the T line, with a LOD as low as 0.1 ng/mL. Compared with the traditional lateral flow immunoassay (LFIA) based on gold sphere nanoparticle SERS immunoprobe, the LFIA based on gap-enhanced SERS immunoprobe has a 30-fold lower LOD for cTnI detection, thus having the ability to detect various myocardial biomarkers more sensitively.
In recent years, magnetic separation and enrichment technology has also been combined with SERS for cTnI detection. For example, Li et al. Developed a strategy of cTnI detection using core-shell SERS probe combined with magnetic separation[118]. They combined antibodies with magnetic beads to construct immunomagnetic beads that can specifically capture cTnI. The SERS immunoprobe was prepared by embedding Raman molecule 4MBA between gold core and silver shell and modifying the antibody on the surface of the nanoparticle. Immunomagnetic beads, cTnI and SERS immunoprobe were combined to form a sandwich complex, and finally the beads were controlled by an external magnetic field to separate and enrich the immune complex, and then the cTnI in the sample was detected by SERS, with a LOD as low as 9. 80 pg/mL. The strategy does not require a complex sample separation and purification process, and is simple to operate, small in sample size, fast in detection, and high in sensitivity in combination with a portable Raman instrument. In order to evaluate the clinical utility and diagnostic ability of the sensor, they used SERS and FDA approved clinical chemiluminescence immunoassay to analyze serum samples from 50 hospitalized patients with AMI.The results showed that there was no statistical difference between the two methods, and there was a good correlation, which could meet the requirements of point-of-care testing (POCT). Similarly, Garza et al. Realized the determination of cTnI by using SERS immunoprobe, cTnI antibody-functionalized immunomagnetic beads, and a polydimethylsiloxane (PDMS) enrichment device[119]. As shown in fig. 5, the silver nanoparticles modified with DTNB are coated with silica and then combined with the antibody to prepare the SERS immunoprobe; The antibody is combined with the magnetic bead to construct the immunomagnetic bead with the function of specifically capturing cTnI. After the SERS immunoprobe, cTnI and immunomagnetic beads formed a sandwich immunostructure, a magnetic field was applied to separate the magnetic beads from the free SERS immunoprobe, and then the supernatant was dropped onto the PDMS enrichment device to determine the SERS signal, thus realizing the quantitative detection of cTnI, with a LOD as low as 3. 7 pg/mL. SERS-based magnetic enrichment immunoassay has the advantages of enriching and separating target antigens from complex biological matrices without complex sample pretreatment, improving the speed and accuracy of detection, further improving the detection performance of SERS, and providing a highly sensitive technology for the early diagnosis of AMI.
Different from immune recognition, Ban, Kang and Kim et al. Proposed a method for the determination of cTnI by SERS based on Au nanoplate detection substrate and aptamer recognition mechanism[120]. As shown in Fig. 6 (A), they fixed the aptamer molecule of cTnI on the Au nanoplate to construct the detection substrate, and modified the Raman reporter molecule (Cy5) and the aptamer molecule on the surface of Au NPs to prepare the SERS aptamer probe for detecting cTnI. When cTnI is present, a sandwich structure of "Au nanoplate-cTnI-SERS aptamer probe" is formed, and the highly sensitive and specific detection of cTnI is realized by measuring the SERS signal of the sandwich complex. The results showed that the limit of detection (LOD) of cTnI in buffer solution and serum was 2.4 fg/mL and 2.4 pg/mL, respectively. In addition, they applied the aptamer-immobilized Au nanoplate to the clinical diagnosis of AMI, and tested 9 clinical samples (3 samples from healthy people and 6 samples from AMI patients). The results showed that the concentration of cTnI measured by SERS was consistent with that measured by ELISA. Both methods showed that the concentration of cTnI in healthy people was relatively low, while the concentration of tnI in AMI patients was relatively high. This method can provide more accurate diagnostic results in low concentration of tnI samples. In addition, Li et al. Reported a SERS quantitative detection method for cTnI in human serum using a bimetallic magnetic substrate bound to an aptamer[121]. As shown in Fig. 6 (B), firstly, 3-hydroxytyramine hydrochloride (DA) was coated on the surface of ferroferric oxide particles (Fe3O4), and Ag could deposit on the surface of Fe3O4 through the polydopamine (PDA) layer formed by DA oxidation self-polymerization to form a composite Fe3O4@Ag, then a layer of DA was coated on the composite surface, and Au was fixed on the composite Fe3O4@Ag surface through the PDA layer to prepare a bimetallic magnetic substrate (Fe3O4@Ag@Au); Then the aptamer was modified by Au-S bond on the bimetallic magnetic substrate to form the SERS magnetic capture probe. Based on the specific binding of "aptamer-target protein", the magnetic SERS probe was used to separate the enriched target protein cTnI and then combined with the Raman signal molecule Coomassie brilliant blue G250 (CBBG, which can bind to basic amino acids in cTnI protein) to quantify the concentration of cTniI in serum, with a LOD of 5. 50 pg/mL. In addition to SERS probe detection, aptamer-based label-free SERS detection protocols have also been used to facilitate the detection of myocardial markers. In the label-free method, Raman reporter molecules and SERS probes are not needed, and the aptamer is used to specifically recognize the analyte to cause the change of its own Raman signal, so as to realize the detection of the analyte[115].
It can be seen that the SERS biosensor based on immune recognition or aptamer recognition has high sensitivity in the determination of cTnI, and the detection limit is far below the clinical critical value for the diagnosis of AMI, which shows significant technical advantages in the detection of myocardial biomarker cTnI.

4.2.2 CK-MB assay

In addition to the detection of cTnI by SERS, the detection of CK-MB based on SERS technology has also been reported. For example, Khor et al. Proposed a SERS microfluidic paper-based device (μPAD) for quantitative detection of CK-MB[122]. As shown in fig. 7, tert-butylhydroquinone was used as a Raman reporter molecule to bind to the surface of urchin-like gold nanoparticles, and was wrapped with a silica shell to further modify the monoclonal antibody to prepare the SERS immunoprobe. CK-MB was captured by μPAD modified with monoclonal antibody (immunodetection substrate) and then combined with SERS immunoprobe to form a sandwich immunostructure, and finally CK-MB was quantitatively detected by SERS signal. This SERS-based μPAD can detect CK-MB in the linear range of 0.01 – 100 ng/mL with LOD as low as 10 pg/mL. In addition, they applied the SERS detection device to detect clinical serum samples, and the results of SERS detection were consistent with those of chemiluminescence immunoassay, which proved the reliability of clinical application.
CK-MB is also one of the myocardial biomarkers used to detect AMI. Although it is present in large amounts in skeletal muscle, it is also present in small amounts in other organs, such as the small intestine, uterus, prostate, and diaphragm[123]. In addition, the concentration of CK-MB in the blood will also increase in the case of cocaine abuse, so CK-MB lacks high specificity for AMI, and needs to be combined with other myocardial biomarkers to provide more accurate and comprehensive information for the diagnosis of AMI[124].

4.2.3 Myo detection

In the detection of myocardial biomarker Myo (Mb), new detection technologies based on SERS have been developed and shown excellent detection performance. For example, Du and Gong et al. Have developed Ag@SiO2SERS probes that can detect Mb in combination with silicon wafers[125]. As shown in Fig. 8, they modified Raman reporter 4MBA on the surface of Ag nanoparticles and then wrapped it with SiO2, and then modified glutaraldehyde (GA) on the surface of composite particles to prepare Ag@SiO2SERS probes, which could specifically capture Mb through GA covalent bond. Iminodiacetic acid (IDA) is modified on the surface of silicon wafer to form a capture substrate. When Mb is present, it can be specifically captured by the substrate through coordination interaction, and then combined with the SERS probe to form a "sandwich" immunodetection structure, which uses the SERS signal to detect Myo with a LOD as low as 1.5 ng/mL. The Ag@SiO2SERS probe shows excellent stability in a high-concentration salt environment and long-term storage. For example, El-Said et al. Developed an indium tin oxide substrate (Ag NPT/ITO) with surface modified silver nano-film, and further constructed a SERS sensor for Myo detection[126]. They prepared the Ag NPT/ITO substrate by electrochemically depositing Ag on the ITO surface, and the Ag NPs could directly interact with the heme group of Myo without using any cross-linker. The Ag NPT/ITO substrate modified with the Raman reporter molecule R6G can realize the SERS detection of Myo in solution by using the Raman signal of the planar skeleton of the heme group vibrating at the 1590 cm-1 in the SERS spectrum after Myo is trapped, and the LOD is as low as 10 ng/mL.
In addition, Sabherwal et al. Fabricated a SERS biosensor using aptamer combined with tungsten disulfide gold nanoparticles (AuNP-WS2) to achieve sensitive detection of Myo[127]. As shown in Fig. 9, they assembled AuNPs and Raman reporter R6G on WS2 nanosheets, and further modified the aptamer on the AuNPs on the substrate surface to form a capture substrate capable of specifically capturing Myo. The target analyte Myo exposed to the capture substrate further promotes the charge transfer mechanism through the interaction with the aptamer base, resulting in a significantly enhanced Raman signal on the substrate under 532 nm laser irradiation, and the signal intensity increases with the increase of the concentration of Myo in solution, with a LOD of 10 ng/mL.
The LOD of the SERS biosensor for Myo assay reported in the current literature is at the level of 10 ng/mL, which is far below the clinical cutoff for the diagnosis of AMI. These biosensors developed for the detection of Myo using SERS technology in combination with other nanomaterials enable long-term monitoring of myocardial biomarkers, opening new avenues for their real-time application in the clinical diagnosis of AMI.

4.2.4 Joint detection

As mentioned above, a variety of SERS detection methods for different myocardial biomarkers have been developed, but cTnI, CK-MB and Myo are not only present in cardiac tissues, but also distributed in other tissues, lacking a high degree of tissue specificity. In addition, in different periods of AMI, the change characteristics of different markers are different, and the time span of sharp increase in concentration is also different[21]. Therefore, it is very important to establish a rapid method to detect two or more myocardial biomarkers at the same time for the accurate diagnosis of AMI.
In 2014, Choo et al. First reported an immunoassay for simultaneous detection of cTnI and CK-MB based on SERS combined with magnetic separation and enrichment technique[128]. As shown in Fig. 10 (A), the monoclonal antibodies of cTnI and CK-MB were immobilized on the magnetic beads to form immunomagnetic beads, and the Raman reporter molecules malachite green isothiocyanate (MGITC) and X-rhodamine-5- (and-6) -isothiocyanate (XRITC) were respectively bound to the surface of hollow gold nanospheres (HGN), and then coupled with the two antibodies of cTnI and CK-MB, respectively, to prepare two SERS immunogens for detecting cTn. When the free target antigen, the two SERS immunoprobes and the immunomagnetic beads are mixed at the same time, the antigen will specifically bind to the magnetic beads and the monoclonal antibody on the SERS probes to form a sandwich structure complex. The immune complexes were separated by an external magnetic field, and the Raman signals of the SERS probe in the complexes were measured to quantitatively detect cTnI and CK-MB, with LOD of 33. 7 pg/mL and 42. 5 pg/mL, respectively. They further carried out a study on the detection of clinical serum samples, that is, first, SERS detected cTnI and CK-MB with known different concentrations, and generated calibration curves for the detection of the two myocardial biomarkers, and then SERS measured cTnI and CK-MB in the serum of different patients, and quantified the concentrations of cTnL and CKMB in the serum of patients according to the calibration curves. The results showed that the detection value of SERS immunosensor was in good agreement with that of electrochemiluminescence detection kit. Li et al. Also developed a magnetic immunoassay technique based on SERS for simultaneous detection of H-FABP and cTnI[129]. As shown in fig. 10 (B), the cTnI antibody is combined with the magnetic beads to form immunomagnetic beads, and the Raman reporter molecule 4-mercaptobenzonitrile (4-MP) is embedded between the gold core and the silver shell to form composite particles (Au-4MP @ Ag), which are then combined with the cTnI antibody to obtain the SERS immunoprobe; Similarly, H-FABP antibody was used to modify magnetic beads to obtain immunomagnetic beads, and Raman reporter molecule (XP013) was embedded between gold core and silver shell to form composite particles (Au-XP013 @ Ag) and modify H-FABP antibody to obtain SERS immunoprobe. The "sandwich" immune complex was formed during the detection process, and the concentrations of H-FABP and cTnI were quantified by detecting the characteristic Raman peak intensities of Raman reporter molecules 4MP and XP013 after magnetic field enrichment, and the LOD reached 639. 6 pg/mL and 4. 4 pg/mL, respectively. They used this method to detect 50 clinical serum cTnI samples and 50 H-FABP calf serum samples. SERS measurements of cTnI in clinical samples were compared with chemiluminescent measurements, and H-FABP measurements were compared with previously reported single-marker H-FABP assays, showing thatThere was no statistical difference between the values of cTnI and H-FABP detected by the two methods, and the correlation was good, indicating that the SERS platform has good reliability for the simultaneous detection of cardiac markers cTnI and H-FABP in serum samples.
After the onset of AMI, cTnI can rapidly enter the blood, and its concentration can reach the detectable concentration range within 4 to 6 hours, and the high concentration level will remain for 6 to 8 days. However, the concentration of CK-MB increased after 4 to 6 H and continued to increase within 12 to 24 H[132]. Because of the different characteristics of cTnI and CK-MB, the release time after AMI symptoms is also different, so the simultaneous detection of these two myocardial biomarkers can overcome the disadvantages of detecting a single biomarker and improve the probability of early diagnosis of AMI. For example, Choo and Yu et al. Developed a SERS immunoassay platform based on gold chip for simultaneous detection of cTnI and CK-MB[130]. As shown in fig. 10 (C), a gold chip was prepared by modifying a square AuNPs array on a silicon wafer, and then monoclonal antibodies of cTnI and CK-MB were immobilized on the surface of the gold chip to construct a detection substrate for the detection of the two proteins, and polyclonal antibodies of cTnI and CK-MB were modified on gold core-silver shell (Au @ Ag) nanoparticles, respectively, to prepare two SERS immunoprobes. When cTnI and CK-MB were detected, the "substrate-antigen-SERS immunoprobe" was used to form cTnI and CK-MB sandwich immunocomplexes, respectively, and the characteristic Raman peak intensity of the Raman reporter molecule MGITC immobilized on different regions of the gold chip was monitored for quantitative analysis of cTnL and CK-MB.The LOD was 8. 9 pg/mL and 9. 7 pg/mL, respectively. They further detected cTnI and CK-MB in five clinical serum samples, and the results of SERS were compared with those of commercial chemiluminescence.The concentrations of cTnI and CK-MB measured by SERS immunoassay were in good agreement with those measured by chemiluminescence method within the clinically acceptable range, which confirmed that this SERS binary detection technology has good clinical application potential and can be used as a new tool for AMI screening in vitro. Similarly, Xu et al. Proposed a strategy of optical microcavity combined with SERS to sensitively detect cTnI and CK-MB[131]. As shown in fig. 10 (D), Au NPs were first modified on polystyrene microspheres (PS), and PS was immobilized on the substrate by polydopamine (PDA) to form a PS microcavity, and then monoclonal antibodies of cTnI and CK-MB were immobilized on the Au NPs on the surface of the PS microcavity to construct an immunocapture chip for the detection of the two proteins, respectively; Then the polyclonal antibody of cTnI was combined with Au NPs modified with Raman reporter molecule DTNB, and the polyclonal antibody of CK-MB was combined with Au NPs modified with Raman reporter molecule 4MBA to prepare two SERS immunoprobes. When the target antigen and the two SERS immune probes are present, a "capture chip-target antigen-SERS immune probe" sandwich immune complex is formed; Finally, the concentrations of cTnI and CK-MB were quantified by testing the characteristic Raman signal intensities generated by the modified DTNB and 4MBA on the SERS immunoprobe. The optical confinement effect of the PS microcavity and the LSPR near the Au NPs synergistically enhance the SERS signal, and the optical microcavity-based SERS detection strategy has good specificity, reproducibility, and stability, with LOD of 3.16 pg/mL and 4.27 pg/mL, respectively.
Unlike cTnI and CK-MB released 4 to 6 H after AMI, Myo was released into the blood within 1 to 3 H and reached its maximum concentration within 6 to 12 H[21]. Therefore, rapid quantitative and multiple detection of three myocardial biomarkers, giving full play to the complementary advantages of multi-marker detection in terms of specificity and sensitivity, can obtain meaningful or decisive information through multi-biomarker combined detection, which will reliably monitor AMI and save lives more effectively[133]. At present, point-of-care (POCT) technology, which can quickly and conveniently obtain health information, has become a hot spot in health monitoring, and lateral flow immunoassay (LFIA) is one of the widely used POCT technologies[134]. At present, scientists have developed SERS and LFIA combined detection technology to simultaneously detect Myo, cTnI and CK-MB. For example, in 2018, Zhao et al. First constructed a SERS and LFIA combined detection method to simultaneously and rapidly quantitatively detect Myo, cTnI and CK-MB[135]. As shown in Fig. 11 (a), they prepared three kinds of SERS probes by coupling silver core gold shell nanoparticles (Ag NBA @ Au) with Raman reporter Nile Blue A (NBA) embedded in the gap with antibodies of Myo, cTnI and CK-MB, respectively, and dropped them on the binding pad. The detection antibodies of the three markers are respectively fixed on the three target detection strips to form specific capture probes. When the sample flows from the sample pad to the absorption pad, the three myocardial biomarkers bind to the SERS probe and are captured by the capture probe to form a "sandwich" immune structure when they reach the three target test strips. Finally, the Raman signals of the three test strips are detected to quantify Myo, cTnI and CK-MB. They further measured 50 serum samples collected from AMI patients and compared the results with those measured by the FDA-approved CLIA method, and the results showed that there was a good linear correlation between the two methods for measuring Myo, cTnI and CK-MB. In the same year, Zhao et al. Successfully constructed a single test line of SERS and LFIA methods to detect Myo, cTnI and CK-MB simultaneously[136]. As shown in fig. 11 (B), they encapsulated three Raman reporters (MB, NBA, R6G) in the core-shell gap of silver core-gold shell nanoparticles (Ag @ Au), and then the nanoparticles with different Raman reporters were coupled with Myo, cTnI and CK-MB antibodies to form three SERS immunoprobes. The detection antibodies of the three biomarkers are immobilized on the same target test strip to form a capture probe. In the detection process, a "sandwich" immune structure was also formed on the test strip in the presence of the target, and the SERS signal on the test strip was tested. The concentrations of Myo, cTnI and CK-MB were quantified according to the Raman signals of different characteristic Raman peaks of different Raman reporters, and the LOD was 4.2, 0.89 and 0.93 pg/mL, respectively. The combination of SERS and LFIA has the advantages of rapidity, convenience, low cost, no sample pretreatment, and ultrasensitivity. Multiple myocardial biomarkers can be detected simultaneously by using SERS and LFIA. This ultrasensitive and multiplex SERS combined with LFIA method provides an effective means for accurate clinical early warning and health monitoring of AMI. In addition, they tested five serum samples from AMI patients to verify the clinical reliability of single-T line SERS combined with LFIA, and compared the FDA-approved CLIA method with single-T line combined technique. The results show that the combined technique has good accuracy and good clinical application prospects. Table 1 summarizes the principle and performance indicators of reported SERS myocardial biomarker detection.

5 Conclusion and prospect

Cardiovascular disease (CVD), especially acute myocardial infarction (AMI), is one of the most directly life-threatening diseases in the world. Therefore, quantitative analysis and multi-index detection of myocardial biomarkers (such as cTnI, CK-MB and Myo) will greatly improve the accuracy of AMI detection and save lives more effectively. As a molecular fingerprint spectrum, SERS detection technology has obvious advantages such as convenient and fast detection, low cost, no sample pretreatment, and high sensitivity. Its narrow band characteristics also make it possible to detect multiple myocardial biomarkers at the same time, which can provide more comprehensive, effective and accurate diagnostic information[137][138]. In recent years, SERS sensing technology for rapid and accurate monitoring of myocardial biomarkers in AMI has been reported and has shown great potential for application. At present, SERS myocardial biomarker sensors are mainly constructed based on two recognition strategies, namely immune recognition and nucleic acid aptamer recognition. In the SERS immunodetection technology, a specific antibody capable of recognizing and binding to a target analyte (antigen) is used for biofunctionalization of a detection substrate (construction of an immunodetection substrate), and a SERS immunoprobe is constructed by modifying SERS active nanoparticles with Raman reporter molecules and the antibody.After the detection substrate immunologically recognizes and captures the analyte, the SERS immune probe is immunologically combined with the analyte and bound on the detection substrate to form a sandwich immune detection structure, and the SERS signal of the immune probe is used for detecting the target analyte[139]; In the aptamer-based SERS detection scheme, a high-affinity aptamer capable of specifically binding to an analyte is immobilized on a substrate to prepare a capture unit for recognizing a target protein, and a SERS probe modified with a Raman reporter molecule and an aptamer (SERS aptamer probe) is prepared at the same time.With the help of the "detection substrate-analyte-SERS aptamer probe" sandwich structure complex formed after the detection of the analyte, the SERS spectrum is output under laser excitation, and the detection of the target is realized[140][141]. Although great progress has been made in the detection of myocardial biomarkers in AMI by SERS, there are still many challenges in the detection of myocardial biomarkers and the diagnosis of AMI based on SERS.
On the one hand, although a variety of indicative myocardial biomarkers have been screened out in medicine and used in clinical AMI detection. However, there is a strong and urgent need for early detection of sudden AMI. Reliable early detection is of great practical significance for the prevention of AMI and the effective treatment of AMI patients. In addition, the existing markers still lack sufficient specificity. Therefore, the discovery/screening of new biomarkers that can reflect cardiac injury or acute myocardial infarction earlier and biomarkers with better specificity are the problems that need to be faced and solved for the reliable detection of AMI by SERS technology, which requires the cooperation of scientists and clinicians to overcome the key problems.
On the other hand, SERS technology has the advantages of high sensitivity and specificity, and has a strong ability to detect trace biomolecules in the early stage of disease. Due to the limitation of sensitivity, traditional techniques are unable to detect/screen new early markers. Therefore, how to give full play to the advantages of SERS technology to carry out new early myocardial marker screening for AMI is a research direction of great significance in the future. In addition, although SERS technology has been developed for nearly 50 years and has made gratifying progress in the preparation of SERS active materials, the fabrication of detection devices, the modification of biological functions, and the construction of detection systems, more work is needed in the aspects of universality and personalized design.For example, SERS originates from the localized plasmon resonance on the surface of nanostructures, and the small inhomogeneity of nanostructures will magnify the inconsistency of SERS signals, so the uniformity and repeatability of SERS detection are the bottlenecks for the technology to really enter clinical application. In addition, the individualized design of SERS detection scheme for specific detection objects and the implementation of accurate detection are also the development direction of this technology in the future.

References

Publishing order | Descend order by publishing year | Descend order by cited within
[1]

Ouyang M, Tu D, Tong L, Sarwar M, Bhimaraj A, Li C, CotÉ G L, Di Carlo D. Biosens. Bioelectron., 2021, 171: 112621.
[2]

Virani S S, Alonso A, Benjamin E J, Bittencourt M S, Callaway C W, Carson A P, Chamberlain A M, Chang A R, Cheng S, Delling F N. Circulation., 2020, 141: e139.
[3]

Mythili S, Malathi N. Biomed. Rep., 2015, 3: 743.
[4]

Daubert M A, Jeremias A. Vasc. Health Risk Manag., 2010, 6: 691.
[5]

Thygesen K. Eur. Heart J., 2018, 39: 3757.
[6]

Westermann D, Neumann J T, Sörensen N A, Blankenberg S. Nat. Rev. Cardiol., 2017, 14: 472.
[7]

Sayali U, Ambalika T, Shalini P. Adv. Health Care Technol., 2018, 4: 1.
[8]

Zhang G J, Ning Y. Anal. Chim. Acta., 2012, 749: 1.
[9]

Leisy P J, Coeytaux R R, Wagner G S, Chung E H, Mcbroom A J, Green C L, Williams J W, Sanders G D. J. Electrocardiol., 2013, 46: 92.
[10]

Hoekstra J W, O’neill B J, Pride Y B, Lefebvre C, Diercks D B, Peacock W F, Fermann G J, Gibson C M, Pinto D, Giglio J. Ann. Emerg. Med., 2009, 54: 779.
[11]

Whiting P F, Weswood M E, Rutjes A W, Reitsma J B, Bossuyt P N, Kleijnen J. Bmc. Med. Res. Methodol., 2006, 6: 1.
[12]

Michaelides A P, Dilaveris P E, Psomadaki Z D, Richter D J, Andrikopoulos G K, Pitsilides N, Stefanadis C, Toutouzas P K, Dounis V. Clin. Cardiol., 1999, 22: 403.
[13]

Menown I, Allen J, Anderson J M, Adgey A. Eur. Heart J., 2001, 22: 218.
[14]

Fathil M, Arshad M, Gopinath S C, Hashim U, Adzhri R, Ayub R, Ruslinda A, Nuzaihan M, Azman A, Zaki M. Biosens. Bioelectron., 2015, 70: 209.
[15]

Thygesen K, Alpert J S, Jaffe A S, Chaitman B R, Bax J J, Morrow D A, White H D, Mickley H, Crea F, Van De Werf F. Eur. Heart J., 2019, 40: 237.
[16]

Apple F S, Wu A H, Jaffe A S, Panteghini M, Christenson R H, Members N C, Christenson R H, Apple F S, Cannon C P, Francis G. Circulation., 2007, 116: e95.
[17]

Strimbu K, Tavel J A. Curr. Opin. HIV AIDS., 2010, 5: 463.
[18]

Wang J, Wang X, Ren L, Wang Q, Li L, Liu W, Wan Z, Yang L, Sun P, Ren L. Anal. Chem., 2009, 81: 6210.
[19]

Apple F S, Wu A, Jaffe A S, Panteghini M, Christenson R H, Christenson R H, Apple F S, Cannon C P, Frances G S, Jesse R L. Clin. Biochem., 2008, 41: 222.
[20]

Xu H, Li S, Peng Z, Othman A M, Leblanc R M. Physiol. Plant., 2016, 49: 141.
[21]

Antman E, Bassand J P, Klein W, Ohman M, Sendon J, RydÉn L, Simoons M, Tendera M. J. Am. Coll. Cardiol., 2000, 36: 959.
[22]

Group N W. Clin. Chem., 2007, 53: 2086.
[23]

Bottenus D, Jubery T Z, Ouyang Y, Dong W J, Dutta P, Ivory C F. Lab Chip., 2011, 11: 890.
[24]

Welsh P, Preiss D, Hayward C, Shah A S, Mcallister D, Briggs A, Boachie C, Mcconnachie A, Padmanabhan S, Welsh C J C. Circulation., 2019, 139: 2754.
[25]

Wilkinson J M, Grand R. Nature, 1978, 271: 31.
[26]

Eric C, Christenson R H. Ann. Lab Med., 2013, 33: 309.
[27]

Cummins B, Auckland M L, Cummins P. Am. Heart J., 1987, 113: 1333.
[28]

Panteghini M, Pagani F, Yeo K T J, Apple F S, Christenson R H, Dati F, Mair J, Ravkilde J, Wu A H B. Clin. Chem., 2004, 50: 327.
[29]

Leurent G, Langella B, Fougerou C, Lentz P A, Larralde A, Bedossa M, Boulmier D, Breton H L. Arch. Cardiovasc Dis., 2011, 104: 161.
[30]

Ahammad A, Choi Y H, Koh K, Kim J H, Lee M. Int. J. Electrochem. Sci., 2011, 6: 1906.
[31]

Sörensen N A, Dönmez G, Neumann. J T, Nikorowitsch J, Rübsamen N, Blankenberg S, Westermann D, Zeller T, Karakas M. Biomolecules., 2019, 9: 108.
[32]

Roberts R. Ann. Intern. Med., 1973, 79: 741.
[33]

Collinson P O. Eur. Heart J., 1998, 19: N16.
[34]

Zhang J, Lv X, Feng W, Li X, Li K, Deng Y. Mikrochim. Acta., 2018, 185: 1.
[35]

Jaf Fe A S, Ravkilde J, Roberts R, Naslund U, Apple F S, Galvani M, Katus H. Circulation., 2000, 102: 1216.
[36]

Wilson Tang W, Francis G S, Morrow D A, Newby L K, Cannon C P, Jesse R L, Storrow A B, Christenson R H, Members C, Christenson R H. Circulation., 2007, 116: e99.
[37]

Lai X H, Liang R L, Liu T C, Dong Z N, Wu Y S, Li L H. J Fluoresc., 2016, 26: 987.
[38]

Torabi F, Far H, Danielsson B, Khayyami M. Biosens. Bioelectron., 2007, 22: 1218.
[39]

Thygesen K, Alpert J S, White H D. J. Am. Coll. Cardiol., 2007, 50: 2173.
[40]

Wu D, Chen Y, Hou S, Fang W, Duan H J C. ChemBioChem., 2019, 20: 2432.
[41]

Jaffe A S, Babuin L, Apple F S. J. Am. Coll. Cardiol., 2006, 48: 1.
[42]

Neumann J T, Sörensen N A, Schwemer T, Ojeda F, Bourry R, Sciacca V, Schaefer S, Waldeyer C, Sinning C, RennÉ T. JAMA Cardiol., 2016, 1: 397.
[43]

Sallach S M, Nowak R, Hudson M P, Tokarski G, McCord J. J. Am. Coll. Cardiol., 2004, 94: 864.
[44]

Mair J, Artner-Dworzak E, Lechleitner P, Morass B, Smidt J, Wagner I, Dienstl F, Puschendorf B. Br. Heart J., 1992, 68: 462.
[45]

Mascini M, Tombelli S. Biomarkers., 2008, 13: 637.
[46]

Reyes-Retana J A, Duque-Ossa L C. Curr. Probl. Cardiol., 2021, 46: 100739.
[47]

Qureshi A, Gurbuz Y, Niazi J H. Sens. Actuators B Chem., 2012, 171/172: 62.
[48]

Gomes-Filho S, Dias A, Silva M, Silva B, Dutra R F. Microchem. J., 2013, 109: 10.
[49]

Horak J, Dincer C, Qelibari E, Bakirci H, Urban G. Sens. Actuators B Chem., 2015, 209: 478.
[50]

He H Z, Leung K H, Yang H, Chan S H, Leung C H, Zhou J, Bourdoncle A, Mergny J L, Ma D L. Biosens. Bioelectron., 2013, 41: 871.
[51]

Leung C H, Zhong H J, He H Z, Lu L, Chan S H, Ma D L. Chem. Sci., 2013, 4: 3781.
[52]

Lee J, Lee Y, Park J Y, Seo H, Lee T, Lee W, Sang K K, Hahn Y K, Jung J Y, Kim S. Sens. Actuators B Chem., 2013, 178: 19.
[53]

Liu J, Zhang L, Wang Y, Zheng Y, Sun S. Measurement., 2014, 47: 200.
[54]

Balsam J, Ossandon M, Bruck H A, Lubensky I, Rasooly A. Expert Rev. Mol. Diagn., 2013, 7: 243.
[55]

Ran B, Xianyu Y, Dong M, Chen Y, Qian Z, Jiang X. Anal. Chem., 2017, 89: 6113.
[56]

Juronen E I, Viikmaa M H, Mikelsaar A. J. Immunol. Methods., 1988, 111: 109.
[57]

Jiao L, Zhang L, Du W, Li H, Yang D, Zhu C. Nanoscale, 2019, 11: 8798.
[58]

Dobrovolskaia E, Gam A, Slater J. Clin. Exp. Allergy., 2006, 36: 525.
[59]

Han G R, Kim M G. Sensors, 2020, 20: 2593.
[60]

Pei X, Zhang B, Tang J, Liu B, Lai W, Tang D. Anal. Chim. Acta, 2013, 758: 1.
[61]

Lin Y, Zhou Q, Lin Y, Tang D, Niessner R, Knopp D. Anal. Chem., 2015, 87: 8531.
[62]

Zhang T, Ma N, Ali A, Wei Q, Wu D, Ren X. Biosens. Bioelectron., 2018, 119: 176.
[63]

Zhang B, Zhang Y, Liang W, Yu X, Tan H, Wang G, Li A, Jin J, Huang L. RSC Advances., 2017, 7: 2486.
[64]

Qiao X, Li K, Xu J, Cheng N, Sheng Q, Cao W, Yue T, Zheng J. Biosens. Bioelectron., 2018, 113: 142.
[65]

Lou L, Yu K, Zhang Z, Huang R, Zhu J, Wang Y, Zhu Z. Nano Research., 2012, 5: 272.
[66]

Bailey M R, Pentecost A M, Selimovic A, Martin R S, Schultz Z D. Anal. Chem., 2015, 87: 4347.
[67]

Lu W B, Wang Y, Cao X, Li L, Dong J, Qian W. New J. Chem., 2015, 39: 5420.
[68]

Dodeigne C, Thunus L, Lejeune R. Talanta., 2000, 51: 415.
[69]

Ekins R, Chu F, Micallef J. J. Biolumin. Chemilumin., 1989, 4: 59.
[70]

Cho I H, Paek E H, Kim Y K, Kim J H, Paek S H. Anal. Chim. Acta., 2009, 632: 247.
[71]

Han G R, Kim M G. Biotechnol. Bioprocess Eng., 2019, 24: 206.
[72]

Zhao H, Su E, Huang L, Zai Y F, Liu Y, Chen Z, Li S, Jin L, Deng Y, He N Y. Chin. Chem. Lett., 2022, 33: 743.
[73]

Zhao L, Sun L, Chu X. Trends Analyt Chem., 2009, 28: 404.
[74]

Kurihara T, Yanagida A, Yokoi H, Koyata A, Matsuya T, Ogawa J, Okamura Y, Miyamoto D. Anal. Biochem., 2008, 375: 144.
[75]

Darain F, Yager P, Gan K L, Tjin S C. Biosens. Bioelectron., 2009, 24: 1744.
[76]

Hill H R, Martins T B. Methods., 2006, 38: 312.
[77]

Song S Y, Han Y D, Kim K, Yang S S, Yoon H C. Biosens. Bioelectron., 2011, 26: 3818.
[78]

Xu H, Zhang Z. Biosens. Bioelectron., 2007, 22: 2743.
[79]

Ganesh N, Block I D, Mathias P C, Wei Z, Chow E, Malyarchuk V, Cunningham B T. Opt. Express., 2008, 16: 21626.
[80]

Shen Y, Liu S, Yang J, Wang L, Tan X, He Y. Sens. Actuators B Chem., 2014, 199: 389.
[81]

Chen J, Ran F, Chen Q, Luo D, Ma W, Han T, Wang C, Wang C. RSC Advances, 2019, 9: 4463.
[82]

Hayes M A, Petkus M M, Garcia A A, Taylor T, Mahanti P. Analyst., 2009, 134: 533.
[83]

Wang L H, Song C Y, Zhang L, Zhu D. Nanoplasmonic Materials and Biomedical Applications. Beijing: Beijing Science Press, 2017.
[84]

Elina A, Zul O. ACS Nano., 2009, 3: 3529.
[85]

Lin X M, Cui Y, Xu Y H, Ren B, Tian Z Q. Anal. Bioanal Chem., 2009, 394: 1729.
[86]

Nie S, Emory S R. Science., 1997, 275: 1102.
[87]

Kneipp K, Wang Y, Kneipp H, Perelman L T, Itzkan I, Dasari R R, Feld M S. Phys. Rev. Lett., 1997, 78: 1667.
[88]

Bhardwaj V, Srinivasan S, Mcgoron A. J. Biosens. Bioelectron., 2013, 12: 2.
[89]

Grubisha D S, Lipert R J, Park H Y, Driskell J, Porter M D. Anal. Chem., 2003, 75: 5936.
[90]

Mohs A M, Mancini M C, Singhal S, Provenzale J M, Leyland-Jones B, Wang M D, Nie S. Anal. Chem., 2010, 82: 9058.
[91]

Sha M Y, Xu H, Natan M J, Cromer R. J. Am. Chem. Soc., 2008, 130: 17214.
[92]

Beier H T, Cowan C B, Chou I H, Pallikal J, Henry J E, Benford M E, Jackson J B, Good T A, CotÉ G L. Plasmonics., 2007, 2: 55.
[93]

An J H, El-Said W A, Yea C H, Kim T H, Choi J W. J. Nanosci. Nanotechnol., 2011, 11: 4424.
[94]

Zhang J J, Yang Y J, Jiang X Y, Dong C, Song C Y, Han C Q, Wang L H. Biosens. Bioelectron., 2019, 141: 111402.
[95]

Yang Y J, Jiang X Y, Jie C, Song C Y, Wang L H. Sci. China Mater., 2017, 60: 1129.
[96]

Song C Y, Yang Y J, Yang B Y, Sun Y Z, Zhao Y P, Wang L H. Nanoscale, 2016, 8: 17365.
[97]

Fleischmann M, Hendra P J, Mcquillan A J. Chem. Phys. Lett., 1974, 26: 163.
[98]

Jeanmaire D L, Van Duyne R P. J. Electroanal. Chem. Interfacial.Electrochem., 1977, 84: 1.
[99]

Albrecht M G, Creighton J A. J. Am. Chem. Soc., 1977, 99: 5215.
[100]

Kirtley J, Jha S, Tsang J. Solid State Commun., 1980, 35: 509.
[101]

Park T H, Galperin M. Phys. Rev. B., 2011, 84: 075447.
[102]

Doering W E, Nie S. J. Phys. Chem. B., 2002, 106: 311.
[103]

Song C Y, Yang Y J, Yang B Y, Min L H, Wang L H. J. Mater. Chem. B., 2016, 4: 1811.
[104]

Song C Y, Jiang X Y, Yang Y J, Zhang J J, Larson S, Zhao Y P, Wang L H. ACS Appl. Mater. Interfaces., 2020, 12: 31242.
[105]

Ling X, Xie L, Fang Y, Xu H, Zhang H, Kong J, Dresselhaus M S, Zhang J, Liu Z. Nano Lett., 2010, 10: 553.
[106]

Wang H, Yang R, Yang L, Tan W. ACS Nano, 2009, 3: 2451.
[107]

Ellington A D, Szostak J W. Nature, 1990, 346: 818.
[108]

Tuerk C, Gold L. Science, 1990, 249: 505.
[109]

Li A, Tang L, Song D, Song S, Ma W, Xu L, Kuang H, Wu X, Liu L, Chen X. Nanoscale, 2016, 8: 1873.
[110]

Chung E, Gao R, Ko J, Choi N, Lim D W, Lee E K, Chang S I, Choo J. Lab Chip., 2013, 13: 260.
[111]

Feng J, Wu X, Ma W, Kuang H, Xu L, Xu C. Chem. Commun., 2015, 51: 14761.
[112]

Bamrungsap S, Treetong A, Apiwat C, Wuttikhun T, Dharakul T. Mikrochim Acta, 2016, 183: 249.
[113]

Muhammad M, Huang Q. Talanta, 2021, 227: 122188.
[114]

Lee J H, Yigit M V, Mazumdar D, Yi L. Adv. Drug Deliv. Rev., 2010, 62: 592.
[115]

Porter M, Lipert R J, Siperko L M, Wang G, Narayanan R. Chem. Soc. Rev., 2008, 37: 1001.
[116]

Fu X, Wang Y, Liu Y, Liu H, Fu L, Wen J, Li J, Wei P, Chen L. Analyst., 2019, 144: 1582.
[117]

Khlebtsov B N, Bratashov D N, Byzova N A, Dzantiev B B, Khlebtsov N G. Nano Res., 2019, 12: 413.
[118]

Hu C, Ma L, Mi F, Guan M, Guo C, Peng F, Sun S, Wang X, Liu T, Li J. New J. Chem., 2021, 45: 3088.
[119]

Garza J T, Cote G L. Anal. Chem., 2017, 89: 13120.
[120]

Lee H, Youn H, Hwang A, Lee H, Park J Y, Kim W, Yoo Y, Ban C, Kang T, Kim B. Nanomaterials, 2020, 10: 1402.
[121]

Lin C, Li L, Feng J, Zhang Y, Lin X, Guo H, Li R. Mikrochim Acta, 2022, 189: 1.
[122]

Lim W Y, Goh C H, Thevarajah T M, Goh B T, Khor S M. Biosens. Bioelectron., 2020, 147: 111792.
[123]

Garg P, Morris P, Fazlanie A L, Vijayan S, Dancso B, Dastidar A G, Plein S, Mueller C, Haaf P. Intern. Emerg. Med., 2017, 12: 147.
[124]

Szunerits S, Mishyn V, Grabowska I, Boukherroub R. Biosens. Bioelectron., 2019, 131: 287.
[125]

Kong X, Yu Q, Zhang X, Du X, Gong H, Jiang H. J. Mater. Chem., 2012, 22: 7767.
[126]

El-Said W A, Fouad D M, El-Safty S A. Sens. Actuators B Chem., 2016, 228: 401.
[127]

Shorie M, Kumar V, Kaur H, Singh K, Tomer V K, Sabherwal P. Mikrochim. Acta, 2018, 185: 1.
[128]

Chon H, Lee S, Yoon S Y, Lee E K, Chang S I, Choo J. Chem. Commun., 2014, 50: 1058.
[129]

Hu C, Ma L, Guan M, Mi F, Peng F, Guo C, Sun S, Wang X, Liu T, Li J. Anal. Methods., 2020, 12: 5442.
[130]

Cheng Z, Wang R, Xing Y, Zhao L, Choo J, Yu F. Analyst., 2019, 144: 6533.
[131]

Wang J, Xu C, Lei M, Ma Y, Wang X, Wang R, Sun J. Microchem. J., 2021, 171: 106875.
[132]

Tuteja S K, Kukkar M, Suri C R, Paul A K, Deep A. Biosens. Bioelectron., 2015, 66: 129.
[133]

Jia L, MacDonald J. Biosens. Bioelectron., 2016, 83: 177.
[134]

Farka Z, Juík T, Ková D, Trnková L, Skládal P. Chem. Rev., 2017, 117: 9973.
[135]

Zhang D, Huang L, Liu B, Ni H, Sun L, Su E, Chen H, Gu Z, Zhao X. Biosens. Bioelectron., 2018, 106: 204.
[136]

Zhang D, Huang L, Liu B, Su E, Chen H Y, Gu Z, Zhao X. Sens. Actuators B Chem., 2018, 277: 502.
[137]

Lu W B, Wang Y, Cao X, Li L, Dong J, Qian W. New J. Chem., 2015, 39: 5420.
[138]

Matschulat A, Drescher D, Kneipp J. ACS Nano, 2010, 4: 3259.
[139]

Cheng Z Y, Choi N, Wang R, Lee S, Moon K C, Yoon S Y, Chen L X, Choo J. ACS Nano, 2017, 11: 4926.
[140]

Hori S I, Herrera A, Rossi J, Zhou J H. Cancers, 2018, 10: 9.
[141]

Hassan E M, Willmore W G, Derosa M C. Nucleic. Acid. Ther., 2016, 26: 335.

Funding

National Natural Science Foundation of China(61871236)

PDF (3061KB)

2001

Accesses

0

Citation

Detail
Sections
Recommended

/

〈 〉

Address of Editorial Office: No. 33 Beisihuan Xilu, Zhongguancun , Beijing 100190, China
Tel: +86 10 8262 7757
Fax: +86 10 8262 7757
E-mail: progchem@mail.las.ac.cn
http://www.progchem.ac.cn
    • 　
    Copyright © Editorial Office of Progress in Chemistry