Application and prospect of carbon nanomaterials in electroanalysis for detection of illicit drugs in sports

ABSTRACT

Illicit drug abuse to enhance athletic performance undermine integrity of sports. Detecting banned substances is challenging owing to rapid clearance and evasion via masking agents. Chromatography techniques are constrained by cost, analysis times and portability impeding on-site testing. Electroanalytical sensors incorporating carbon nanomaterials demonstrate vast promise as rapid, sensitive and cost-effective complementary screening tools. Exceptional conductivity, electrocatalysis and functionalization potential of graphene, carbon nanotubes and fullerenes allow parts-per-billion detection limits matching immunological assays for stimulants and anabolics. Aptamer integration also imparts target specificity. Nevertheless, translation from lab prototypes to commercial devices needs optimization of green synthesis protocols and surface stabilization for reliable reproducibility. Coupling to microfluidics and machine learning data harmonization can enable automated sampling, multi-marker testing and wireless result archiving at decentralized point-of-care. Overall, miniaturized nanosensors adequately sensitive for divide cutoff concentrations aid anti-doping enforcement through early interventions, chelation therapy and deterrence against proliferation of doping culture among athletes.

Keywords:
nanosensors; microfluidics; surface functionalization; green synthesis; data harmonization

1. INTRODUCTION

The use of performance-enhancing and illicit drugs to gain an unfair competitive advantage in sports has become a serious issue in recent years [¹]. This unethical practice undermines the integrity of competitive sports and can have severe health impacts on the athletes [²]. Rapid detection and deterrence of drug abuse in sports is therefore essential [³]. However, the detection of illicit drugs in biological fluids poses several challenges due to the short detection window resulting from rapid clearance, metabolization, and elimination of these drugs from the body [⁴, ⁵]. Therefore, highly sensitive, selective, rapid, and easy-to-use analytical methods are needed for on-site monitoring of athletes to detect illicit drug abuse.

In the past, chromatographic techniques such as high-performance liquid chromatography (HPLC) and gas chromatography (GC), coupled with mass spectrometry (MS) [⁶], were predominantly used for detection of illicit drugs and doping agents. However, these techniques require complex sample preparation steps, expensive instrumentation, and trained personnel [⁷]. These requirements make such lab-based techniques unsuitable for rapid, on-site detection necessary in sporting events [⁸]. Electroanalytical methods, especially those employing electrochemical sensors, are emerging as promising alternatives and complementary techniques to chromatographic methods for drug detection applications [⁴].

Electrochemical sensors offer several attractive features such as rapid response, ease-of-use, simple instrumentation, high sensitivity, excellent selectivity, and portability for on-site measurements at low cost [⁹,¹⁰,¹¹]. Carbon nanomaterials such as carbon nanotubes (CNTs), graphene, and fullerenes have gained immense interest in recent years as electrode materials for electrochemical devices due to their unique structural, electrical, optical and electrocatalytic properties [¹²]. The high surface area, electrical conductivity, mechanical strength, and ability to promote electron transfer reactions make carbon nanomaterials excellent electrode materials for developing highly sensitive electrochemical sensors [¹³]. Additionally, the possibility of surface functionalization of carbon nanomaterials allows selective detection even in complex sample matrixes [¹⁴]. There is extensive research focused on developing electroanalytical methods based on carbon nanomaterial modified electrodes for rapid, sensitive and selective detection of illicit drugs relevant to sports.

This review aims to provide a critical assessment of the promises and prospects of carbon ­nanomaterial-based electroanalytical techniques for sensitive detection of illicit sports drugs in complex biological fluids. The objectives of this review are three-fold – (1) to provide an overview of the categories of illicit drugs relevant to sports and challenges in their detection (2) to outline the developments and advances in carbon nanomaterial-based electrochemical sensors for drug detection (3) to discuss the opportunities and future directions to enable practical implementation of such sensors for routine anti-doping analysis and on-site detection of drug abuse in sports.

The review is structured into eight main sections. The first section introduces illicit drug use in sports and associated challenges. This is followed by an overview of conventional and electroanalytical techniques for drug detection in Section 2 and 3, focusing on their merits and limitations in the context of application for anti-doping analysis in sports. Section 4 summarizes the exceptional properties of carbon nanomaterials including CNTs, graphene, and fullerenes along with common functionalization approaches to enhance their sensing performance. The recent advances in the synthesis, characterization and applications of these nanomaterials are concisely reviewed. Section 5 provides a detailed assessment of the fabrication principles as well as sensing capabilities of CNT, graphene and fullerene-based electrochemical sensors for relevant illicit sports drugs. The current challenges and future prospects in terms of advanced electrode architectures, commercialization feasibility and recent research directions are critically discussed in Section 6. Finally, the major conclusions arising from this review along with an outlook on future research needs are presented.

2. ILLICIT DRUGS IN SPORTS

Several categories of drugs are abused by athletes to enhance performance or provide an unfair advantage over competitors in sports (Figure 1). Stimulants such as amphetamines, cocaine, and caffeine are the most common drugs used illegally by athletes across various sporting disciplines to delay fatigue, improve alertness, and boost competitive performance levels [¹⁵]. For instance, amphetamine increases the availability of catecholamines which heightens arousal, focus, and aggression levels while delaying fatigue – effects deemed favorable for gaining a competitive edge [¹⁶]. Other common stimulants in sports include ephedrine and strychnine [¹⁷, ¹⁸]. Several anabolic steroids such as nandrolone, stanozolol, and testosterone are also consumed to accelerate muscle growth, power output and recovery from injury [¹⁹,²⁰,²¹]. Narcotic analgesics including morphine, methadone, heroin and other opioid agonists allow athletes to ignore or play through pain and injuries by raising the pain threshold [²²,²³,²⁴,²⁵]. Sedatives such as barbiturates, benzodiazepines, clonidine and antidepressants are helpful for sportspersons to relieve pre-competition anxiety, stress, and tension [²⁶,²⁷,²⁸,²⁹]. Diuretics such as f­­urosemide, spironolactone, and mannitol artificially lower body weight for achieving weight classification ­requirements in weight-categorized sports events [³⁰,³¹,³²].

Figure 1
Categories of drugs are abused by athletes.

Other supporting or masking agents are also popular in sports to conceal the presence of primary performance enhancing chemicals during drug testing. These include epitestosterone (lowers testosterone/­epitestosterone ratio) [³³], probenecid (delays excretion of steroids) [³⁴] and plasma expanders such as albumin [³⁵], dextran [³⁶] and mannitol (dilutes drug residues) [³⁷]. The short detection window for many of these illicit drugs in biological fluids resulting from rapid clearance, distribution and elimination creates a need for highly sensitive, selective and field-deployable drug testing techniques to prevent their abuse in sports competitions. Despite stringent testing protocols and monitoring programs by sports federations, the continued usage of ­masking chemicals further necessitates development of novel analytical tools for reliable on-site anti-doping analysis and testing.

The use of illicit performance-enhancing drugs can have severe deleterious effects on the health and well-being of athletes. Anabolic steroids, for instance, are linked with several psychiatric effects including aggression, violence, mania and depression as well as physiological side effects such as liver tumors, kidney failure, heart attacks, strokes and blood clots [³⁸]. Stimulants like amphetamines and cocaine are associated with cardiovascular complications, seizures, hyperthermia and even sudden death especially when combined with intense physical exertion in competitive sports [³⁹, ⁴⁰]. Narcotic analgesics and sedatives also have a high potential for addiction and dependence in the long term [⁴¹]. Diuretics lead to dehydration and electrolyte imbalances like hypokalemia, hyponatremia and metabolic alkalosis. Other adverse effects include nausea, dizziness, cramping and diarrhea [⁴²].

In addition, the unfair advantage gained by drug-cheating athletes destroys integrity and sportsmanship of competitions [⁴³]. Unfair victories and broken records compromise credibility and questions remain regarding achievements of even clean athletes [⁴⁴]. It also coerces other athletes to consume banned substances merely to remain competitive. This implicitly pressures athletes into voluntarily risking their health, career longevity, and public image. Aggressive marketing tactics of illegal sports supplements further tempt usage among athletes [⁴⁵]. High costs of testing, issues with detection windows and accuracy of analytical techniques make enforcement challenging. Harmonizing policies on availability and prohibition of various performance enhancers across countries is also difficult. Despite knowledge of health risks, ambitions for victory and peer pressure lead athletes astray by rationalizing drug usage [⁴⁶]. Stricter penalties, education programs, role models and emphasis on clean victories are essential to curb proliferation of doping culture in sports. Advancements in rapid, accurate and portable detection techniques can aid anti-doping efforts by enabling reliable on-site testing [⁴⁷].

The detection of illicit and banned substances in biological fluids poses several inherent analytical challenges. Many performance-enhancing drugs are rapidly metabolized and eliminated from the body, owing to processes such as distribution into tissues, enzymatic biotransformation, conjugation reactions and renal excretion [⁴⁸]. For example, erythropoietin is produced in the kidney in response to hypoxia and circulating erythropoietin levels [⁴⁹]. As a hormone, erythropoietin enters the bone marrow and binds to erythropoietin receptors on erythroid burst-forming units (BFU-E) and colony forming units (CFU-E). This triggers cell signaling pathways like JAK2/STAT5 that stimulate proliferation, differentiation and survival of red blood cell precursors (Figure 2). The first generation of erythropoietin are rapidly eliminated with short half-lives under 24 hours. Modifications in later generations substantially extended the half-life to allow less frequent dosing. But the paper does not provide specifics on the metabolic pathways or rates of metabolism for these agents. The focus is more on detection timeframes due to differences in elimination rates. This leads to very short detection windows ranging from a few hours to a couple of days for many banned stimulants, anabolics, narcotics and diuretics. Masking agents further enable drugs to evade detection via immunoassays, thin layer chromatography tests and mitigating concentration levels in urine below cut-off thresholds [⁵⁰]. The continual influx of new designer steroids and unapproved supplements also makes compiling exhaustive banned substance lists difficult [⁵¹]. Sample collection timing and test scheduling can enable cheating athletes to discontinue drug usage well in advance to avoid positive detection. Moreover, issues with storage stability, transportation logistics and integrity checks during transit from collection site to accredited laboratories reduces chances of exposing cheating instances. The lack of harmonization in laboratory testing protocols, sampling criteria, minimum required performance limits and result interpretation procedures further hampers global anti-doping efforts. Advancements in complementary, confirmatory and alternative rapid, on-site analytical techniques are therefore vital for reliable detection of broad categories of illicit and banned sports drugs.

Figure 2
Schematic model of the control of red blood cell production and the sites of action of erythropoiesis-stimulating agents [⁴⁹].

3. CONVENTIONAL DETECTION TECHNIQUES

Chromatographic and spectroscopic analytical techniques have been traditionally relied upon for detection of illicit and banned substances in biological samples collected from athletes. These techniques provide sensitive, accurate and quantitative confirmation of prohibited drugs and doping agents with excellent specificity. GC and HPLC coupled to MS detection are universally considered gold standards for doping control analysis [⁵²,⁵³,⁵⁴].

GC-MS methods offer high resolution separation and enable both screening as well as targeted identification and quantification of various drug compounds and metabolites [⁵⁵]. Derivatization procedures allow enhancement of volatility and thermal stability of non-volatile banned drugs and conversion to detector-responsive derivatives [⁵⁶]. HPLC-MS provides versatile analysis of thermolabile and high molecular weight pharmaceuticals in biological matrices. Availability of user-friendly software with reference mass spectral libraries aids identification and confirmatory analysis. Various sample pretreatment procedures have been standardized including immunoaffinity column extraction [⁵⁷], liquid-liquid extraction [⁵⁸], protein precipitation [⁵⁹] and solid phase extraction [⁶⁰] techniques for removal of matrix effects in urine, blood and oral fluid samples. These chromatography hyphenated MS platforms have additional advantages such as retrospective data analysis, method development feasibility and potential to detect unknown or emerging doping agents.

However, GC-MS and HPLC-MS techniques have some critical limitations in context of routine anti-doping screening and testing programs implemented in professional and college-level sports [⁶¹]. The high equipment costs, infrastructural overheads of maintaining accredited laboratories and need for expert personnel significantly increase per-sample analysis charges posing economic constraints [⁶²]. The multi-step protocols also involve lengthy sample preparation and long chromatographic run times ranging from 30 minutes to over 1 hour leading to reporting delays of 4–6 weeks. This lag period enables cheating athletes to participate in multiple competitions before a positive finding is confirmed [⁶³]. The lack of portability of benchtop instruments restricts testing on-site at sporting venues or training camps which facilitates premeditated cheating by ­temporary drug discontinuation [⁶⁴]. There are also ethical concerns regarding false positives arising from contamination, positional isomers, relaxed testing criteria and improper validation of analytical methods. Hence alternative rapid, field-deployable and cost-effective techniques that complement chromatographic verification are being actively researched for drug abuse monitoring in sports.

4. ELECTROANALYTICAL TECHNIQUES

Electroanalytical techniques are emerging as viable alternatives and complementary methods to chromatographic verification procedures for rapid, sensitive and cost-effective detection of banned substances in anti-doping analysis [⁶⁵,⁶⁶,⁶⁷,⁶⁸,⁶⁹,⁷⁰,⁷¹,⁷²]. Such techniques analyze target analytes based on their oxidation/reduction reactions or electrolysis processes at electrode interfaces. The fundamental principle involves measurement of current, potential or impedance as a function of the concentration of electroactive species [⁷³]. Various voltammetric methods, potentiometry, amperometry and electrochemical impedance spectroscopy have been explored for detection of illicit drugs and doping agents in biological fluids [⁷⁴].

Among electroanalytical methods, voltammetry offers highly sensitive qualitative and quantitative examination of banned drugs in sports that undergo oxidation or reduction reactions [⁷⁵]. Voltammetric analysis measures the current developed in an electrochemical cell under conditions where voltage is varied [⁷⁶]. For example, GOYAL et al. [⁷⁷] investigated the electrochemical behavior of the nandrolone using cyclic, differential pulse and square-wave voltammetry. They modified a glassy carbon electrode (GCE) with a partially reduced fullerene-C60 film to enhance detection sensitivity. Results showed the modified electrode greatly lowered the oxidation peak potential for nandrolone and increased the peak current compared to a bare electrode (Figure 3A), indicating the fullerene film’s electrocatalytic activity. The oxidation process was determined to be irreversible and diffusion-controlled. Using square-wave voltammetry, the method exhibited a linear detection range of 50 μM to 0.1 nM and a detection limit of 0.42 nM for nandrolone. Amperometric techniques monitor current changes over time at a constant potential when target analytes undergo electrolysis at electrode surfaces [⁷⁸]. Potentiometric measurements using ion-selective electrodes, coated wire electrodes and field effect transistors determine equilibrium potential changes proportional to the concentration of charged drug species [⁷⁹]. Conductometric approaches track alterations in the electrolytic solution conductivity caused by banned drugs [⁸⁰]. Electrochemical impedance spectroscopy (EIS) has also offered simple, rapid and portable detection of doping agents through resistive/capacitive changes at electrode interfaces induced by redox-recative analytes [⁸¹]. For example, LIU et al. [⁸²] developed an electrochemical biosensor for the ultrasensitive detection of testosterone. The sensor utilized a nanosized molecularly imprinted polymer film electrochemically grafted onto graphene oxide (GO) nanosheets modified on an electrode. EIS was employed to detect testosterone at the sensor interface (Figure 3B). EIS allowed sensitive transduction of the recognition signal upon rebinding of testosterone to imprinted sites in the polymer film. The GO provided a high surface area and abundant binding sites, enhancing sensitivity. The sensor had a broad linear detection range from 1 fM to 1 μM of testosterone. An extremely low limit of detection of 0.4 fM was achieved. The sensor also demonstrated excellent selectivity over structurally similar hormones, good reproducibility of 3.65%, stability over 30 days, and ability to be regenerated at 96% of initial response. Analysis of spiked human serum samples gave recoveries of 98–104%. Given the high sensitivity, selectivity, reproducibility and stability, this imprinted electrochemical biosensor could provide a promising alternative to testosterone immunosensors for applications in clinical diagnosis.

Figure 3
(A) Typical CVs observed for 1.0 μM nandrolone in PBS of pH 7.2 at a bare (- - -) and fullerene-C60-modified (—) GCE electrode [⁷⁷]. (B) The EIS response of the MIP/GO electrode towards testosterone in different concentrations [⁸²].

Compared to chromatographic methods, electroanalytical strategies provide rapid analysis, cost-effectiveness and portability since expensive supporting instrumentation is not necessary. Miniaturized and integrated lab-on-a-chip devices enable collection of samples such as saliva and sweat along with electrochemical quantification on a single platform within minutes [⁸³]. The high sensitivity ranging from sub-nanomolar to micromolar concentration detection matches or exceeds performance of conventional techniques. Multiple banned categories of pharmaceuticals can also be simultaneously detected in a single measurement. For example, PARRILLA et al. [⁸³] presented an electrochemical device using disposable screen-printed electrodes (SPEs) for the rapid on-site detection of common illicit drugs (Figure 4). They first built an electrochemical profile library of pure drug standards and cutting agents under various pH conditions to determine the optimal electrochemical “fingerprint” of each drug. This library was integrated into an identification algorithm. Next, they tested the device by analyzing 48 real confiscated drug samples and comparing results to gas chromatography-mass spectrometry. The electrochemical device successfully detected the target drug in 45 out of 48 samples, achieving 93.8% accuracy. Performance was benchmarked against a portable Raman spectrometer (58.3% accuracy) and compact FTIR device (85.4% accuracy). Data processing is simplified without extensive spectral deconvolution and validation protocols. Techniques such as stripping voltammetry also offer low detection limits via analyte preconcentration.

Figure 4
Rapid on-site detection of illicit drugs with a portable electrochemical device [⁸³].

However limitations such as selectivity in complex matrices, reproducibility and electrode surface fouling effects need consideration. Stringent validation requirements, interference from coexisting benign substances in biological fluids and requirement of sample deproteinization can challenge field applicability. Non-­specific adsorption and passivation restrict sensor longevity requiring surface modifications [⁸⁴]. ­Nevertheless, ­exploiting novel nanomaterial interfaces and conducting matrices offers tremendous scope for devising rapid, reliable and targeted electroanalytical devices for on-site, high throughput anti doping screening applications.

5. CARBON NANOMATERIALS

Carbon nanomaterials are emerging as attractive electrode interface modifiers for designing electrochemical sensors and biosensors owing to their exceptional thermal, mechanical and electrocatalytic properties [⁸⁵]. The discovery of fullerenes, carbon nanotubes and isolation of single-to-few layer graphene has expanded possibilities for novel carbon allotropes with unique architecture-dependent electronic, optical and magnetic characteristics (Figure 5). The high surface area, excellent conductivity, good biocompatibility, ease of surface functionalization and stability of carbon nanostructures offer new prospects for electroanalysis of challenging biomarkers and low abundance disease signatures [⁸⁶].

Figure 5
Timeline of carbon nanomaterials.

Graphene is a single sheet of sp² hybridized carbon atoms densely packed in a two-dimensional honeycomb lattice conferring exceptional mechanical strength, thermal conductivity, mobility of charge carriers and specific surface area. It serves as an ideal support to immobilize recognition moieties and anchor metallic nanoparticles without impairing bioactivity [⁸⁷]. GO, a derivative bearing oxygen-containing functional groups, enables covalent bioconjugation and solubility in aqueous media. Reduced forms of GO (RGO) offer excellent conductivity for rapid electron transfer. CHAUDHARY et al. [⁸⁸] reviewed research on molecules immobilization using GO and RGO as solid support materials over the past decade. GO and RGO have features like high surface area, surface functional groups, and hydrophilicity that make them suitable for molecules immobilization without surface modification. The main driving forces for molecules binding are non-covalent interactions like hydrogen bonding, electrostatic interactions, hydrophobic interactions, and van der Waals forces. Covalent immobilization is also possible. These interactions influence protein conformation, activity, and stability (Figure 6).

Figure 6
Predominant interactions involved between immobilized molecules and GO/RGO [⁸⁸].

CNTs composed of rolled up graphene sheets display rapid electrode kinetics owning to ballistic electron transport and possess high tensile strength for immobilizing biomolecules via non-covalent π-π stacking interactions [⁸⁹, ⁹⁰]. Metallic single walled CNTs promote electron transfer between redox enzymes and electrodes due to electrocatalytic effects. The thermal and chemical robustness of multiwalled CNTs (MWCNTs) improve sensor longevity without loss of signal reproducibility. However, CNTs tend to aggregate due to strong van der Waals interactions between the tubes. This can reduce the effective surface area and negatively impact the sensitivity of the sensor [⁹¹]. Synthesizing MWCNTs with controlled properties (e.g., number of walls, oxygen content) is challenging [⁹²]. Lack of precise control can lead to variations in sensor performance and reproducibility issues [⁹³]. CNTs functionalized with carboxylic, amino or polymeric groups enable covalent bioconjugation while enhancing solubility and compatibility. For example, PENG et al. [⁹⁴] developed a sensitive electrochemical sensor using a GCE modified with CeO₂/CNT nanocomposite to detect the presence of methyltestosterone as a doping agent in sports. The CeO₂/CNT nanocomposite was synthesized via a solvothermal method. Characterization results showed that the CeO₂ nanoparticles were successfully anchored onto the CNTs. Electrochemical testing revealed that attaching CeO₂ nanoparticles to the hierarchical porous structure of interconnected CNTs with a high surface area amplified the signal for methyltestosterone detection. The sensor exhibited excellent selectivity towards methyltestosterone with negligible responses to various interfering chemicals tested. It demonstrated a sensitivity of 8.5992 μA/μg·mL⁻¹, a broad linear detection range of 0–10 μg/mL methyltestosterone, and a low limit of detection reaching 0.3 ng/mL.

Fullerenes composed of wrapped graphene with a caged motif exhibit reversible multi-electron transfer capacity useful for enzyme wiring. The spherical structure offers a rigid scaffold for fabricating molecularly imprinted polymer films [⁹⁵]. Composite forms along with metallic nanoparticles, enzymes and conducting polymers enhance electron flux. Other carbon nanodots [⁹⁶], nanohorns [⁹⁷], nanoonions [⁹⁸] and nanodiamonds [⁹⁹] also offer higher edge plane defects enriching electrocatalysis.

Hybridization of different carbon nanomorphologies provide synergistic benefits in electroanalysis. For example, LI et al. [¹⁰⁰] developed a new voltammetric sensor for detecting morphine based on an ­electrochemically reduced MWCNT doped GO composite film (Figure 7) on a GCE. CV and chronocoulometry experiments showed the sensor had good sensitivity towards morphine oxidation, with a wide linear range from 7 × 10⁻⁸ to 1.7 × 10⁻⁵ M and a low detection limit of 5 × 10⁻⁸ M. The sensor could selectively detect morphine even in the presence of common interfering compounds like dopamine, uric acid and codeine. The sensor was successfully applied to detect spiked morphine in human blood serum and urine samples, with recoveries of 98.08% and 100.7% respectively.

Figure 7
(A) The photos of 10 μL GO (a), MWNT (b), MWNT-doped-GO (c) casted on ITO glass; SEM images of GO (B), MWNT (C), MWNT-doped-GO (D) casted on Si plate.

However agglomeration issues, lack of control on layer number, reproducing oxygen content and scale up feasibility currently impedes widespread penetration [¹⁰¹]. High basal plane inertness of pristine graphene and small edge-plane fraction poses bioconjugation issues [¹⁰²]. Defect-induced leakage currents, stability under diverse environments and interference from sample matrices requires appraisal [¹⁰³]. Toxicity concerns arising from impurities and sharp morphologies also merit careful risk-based investigation to realize successful translation into reliable point-of-care devices for drug testing in sports [¹⁰⁴].

6. CARBON NANOMATERIAL-BASED ELECTROCHEMICAL SENSORS

Owing to their exceptional electrocatalytic properties, carbon nanomaterials have attracted tremendous interest in constructing electrochemical sensors and biosensors for rapid and ultrasensitive screening of banned substances in anti-doping analysis. Graphene, carbon nanotubes and fullerenes have been extensively explored either as advanced electrode materials replacing conventional solid electrodes or as nanomodifiers to enhance electron transfer, improve detection limits and enable selective detection in complex biological mixtures even without extensive sample preparation.

Graphene-based electrochemical sensors offer rapid detection of anabolic steroids like nandrolone [¹⁰⁵] and testosterone derivatives [⁹⁴] at levels compliant with stipulated cut-off concentrations prescribed in anti-doping protocols due to improved conductivity and higher surface area. KHOO et al. [¹⁰⁶] investigated the detection of caffeine using different chemically modified graphenes (CMGs), including graphite oxide (GPO), GO and electrochemically RGO (ERGO). They compared the analytical performance of these graphene materials to traditional unmodified electrodes like GCE and edge plain pyrolytic graphite (EPPG) through electrochemical analysis. The results showed that ERGO, which had the highest C/O ratio among the tested CMGs, exhibited the lowest oxidation potential for caffeine (1.26 V), the highest sensitivity (8.74 nA/μM) for caffeine detection. ERGO also demonstrated selectivity towards caffeine over the structurally similar compound theophylline. Covalent linking of aptamers further augments selectivity while metallic nanoparticles facilitate immobilization of aptamers without compromising on their binding affinities [¹⁰⁷]. For example, BELUOMINI et al. [¹⁰⁸] developed an electrochemical sensor for detecting D-mannitol based on a MIP film on an electrode modified with RGO and AuNPs. The RGO and AuNPs were electrodeposited onto a GCE to increase the surface area and improve conductivity and electron transfer kinetics (Figure 8A). The MIP film was then electropolymerized onto the AuNP/RGO-GCE using o-phenylenediamine (o-PD) as the monomer and D-mannitol as the template molecule. The imprinted binding sites left in the MIP allowed for selective recognition of D-mannitol from 1.0 × 10^–12 to 2.0 × 10^–11 M with a detection limit of 7.7 × 10^–13 M. The sensor worked through differential blockade of a redox probe with rebinding of D-mannitol into the MIP cavities. GARIMA et al. [¹⁰⁹] developed an ­electrochemical sensor for detecting the drug clonazepam by modifying a SPE with a nanocomposite made of cobalt oxyhydroxide (CoOOH) nanoflakes and RGO. The CoOOH-RGO nanocomposite was synthesized through a simple soft chemistry approach and self-assembled onto the SPE due to non-covalent interactions between the components (Figure 8B). Testing showed the CoOOH-RGO/SPE sensor had excellent electrocatalytic activity and electron transfer kinetics for clonazepam detection attributed to synergy between the CoOOH nanoflakes providing abundant catalytic sites and the conductive RGO sheets enabling charge transfer. Using differential pulse voltammetry, the sensor achieved a wide clonazepam detection range from 0.1–350 μM and a low detection limit down to 38 nM. Table 1 summarizes the recent developed graphene based electrochemical sensor for detection of illicit drugs in sports.

Figure 8
(A) D-mannitol sensor based on MIP on electrode modified with RGO decorated with AuNPs [¹⁰⁸]. (B) An electrochemical sensor based on Co₂O₃/RGO nanocomposite for detection of clonazepam [¹⁰⁹].

Table 1
Summarizes the recent developed graphene based electrochemical sensor for detection of illicit drugs in sports.

SENSOR	ANALYTE	LINEAR DETECTION RANGE	LIMIT OF DETECTION	REAL SAMPLE PERFORMANCE	REF.
Au/GO/GCE	Nandrolone	1 to 100 μM	4 nM	The sensor was used to determine Nandrolone levels in serum and urine samples of athletes who were administered Nandrolone. The results showed good agreement with ELISA kit, with RSD values of 3.10–4.33%.	[110]
DTMIP/C60/MWCNT-Gr-IL/ITO	Nandrolone decanoate and testosterone decanoate	–	0.05 nM for nandrolone and 0.5 nM for testosterone	The biosensor was successfully applied to the analysis of ND and TS in urine samples from bodybuilder athletes and the results showed good agreement with HPLC reference method. Recoveries from spiked urine samples were in the range of 96.3–106% for both analytes.	[111]
MIP/Au/GCE	19-nortestosterone	5 to 95 μM	3 nM	The sensor was used to detect 19-NT in urine samples from athletes who were administered Nandrodek. The results showed good agreement between the amperometric sensor and ELISA kit assay, with relative standard deviations between 3.09–4.38% for the amperometric method.	[107]
MIP on GOsurface	Testosterone	1 fM to 1 μM	0.4 fM	The sensor was used to detect testosterone in diluted human serum samples. Spike recoveries ranged from 98.6% to 104.2%.	[82]
RGO/GCE	Testosterone	2.0 to 210.0 nM	0.1 nM	The sensor was used for quantification of testosterone in biological fluids (urine and plasma) and drug (ANDRONE®100) with good recovery.	[112]
PDA/Au@RGO	Testosterone	25 to 200 μM	4.2 μM	The sensor was used to detect testosterone spiked in pH 7.4 PBS buffer. The electrocatalytic conversion of testosterone to 6β-OH testosterone by the sensor was confirmed using HPLC-MS.	[113]
Graphene-modified SPE	Methamphetamine	1–500 μM	0.3 μM	Street samples containing methamphetamine: Detected methamphetamine in 8 out of 9 samples (89% true positive rate)	[114]
Graphene/AuNP modified electrode	Cocaine	1 nM to 500 nM	1 nM	–	[115]
3D-MRGO/PA/AuNP/aptamer based impedimetric aptasensor	Cocaine	0.09 to 85 nM	0.029 nM	The aptasensor was applied to detect cocaine in spiked urine and serum samples with satisfactory recoveries. Relative standard deviations ranged from 2.4% to 3.9%.	[116]
CRGO-GCE	Furosemide	1–600 μM	0.7 μM	Recovery between 89–99% in spiked seawater samples.	[117]

CNTs integrated electrochemical sensors and biosensors have also offered direct, label-free and reagentless evaluation of narcotic analgesics like morphine and toxic alkaloids. SWCNT forests facilitate rapid electron transfer between redox enzymes and electrodes preserving their tertiary structure and bioactivity [¹¹⁸]. CNT modified SPE allows detection of diuretics such as morphine [¹¹⁹]. YANG et al. [¹²⁰] developed a simple and scalable method to fabricate disposable electrochemical sensors based on SWCNTs using template filtration (Figure 9). They used a portable flash stamp machine and common office printer to make polydimethylsiloxane (PDMS) patterns on polyvinylidene fluoride (PVDF) membranes. These were then used as templates to filter a SWCNT solution and obtain patterned SWCNT electrodes with high conductivity, flexibility and reproducibility. The resulting three-electrode sensor array exhibited excellent electrochemical activity and anti-biofouling capacity compared to traditional GCE when tested with ferro/ferricyanide. It was used to detect the drug morphine, showing good sensitivity from 0.2 to 100 μg/mL, detection limit of 0.06 μg/mL. SONG et al. [¹²¹] developed a new sensor for detecting methadone by modifying a carbon paste electrode (CPE) with poly-L-arginine and CNT (P-L-Arg/CNTs/CPE). They used electropolymerization to coat the CPE surface with a uniform layer of rod-like P-L-Arg structures formed around a network of twisted CNT bundles. Structural analyses showed successful modification of the CPE. CV and amperometry experiments demonstrated that the P-L-Arg/CNTs composite significantly improved sensitivity and selectivity for methadone detection compared to unmodified or single-component modified CPEs. Table 2 summarizes the recent developed CNT based electrochemical sensor for detection of illicit drugs in sports.

Figure 9
Schematic procedures and filtration device structures for preparing SWCNTs electrodes by flash foam stamp-­assisted template filtration [¹²⁰].

Table 2
Summarizes the recent developed CNT based electrochemical sensor for detection of illicit drugs in sports.

SENSOR	ANALYTE	LINEAR DETECTION RANGE	LIMIT OF DETECTION	REAL SAMPLE PERFORMANCE	REF.
CeO2/CNTs/GCE	Methyltestosterone	0–10 μg/mL	0.3 ng/mL	The sensor was tested in real human blood serum samples from athlete volunteers. Suitable recovery values (94.50–98.00%) and acceptable relative standard deviation (RSD) values (3.97–5.03%) were obtained.	[94]
ZnO/CNT	Morphine	0.1 to 700 μM	0.06 μM	Successfully applied to detect morphine in pharmaceutical injection solution and urine samples	[119]
MWNTs-doped GO/GCE	Morphine	0.07–17 μM	0.05 μM	Tested in human blood serum and urine samples, recoveries ranged from 91.2–100.3% in serum and 94.2–106.3% in urine.	[100]
NiO/CNTs ionic liquid CPE	Morphine	0.05–520 μM	0.01 μM	The sensor was successfully applied for the determination of morphine in injection solution and urine samples. The results showed good recovery and accuracy.	[122]
P-L-Arg/CNTs/CPE	Methadone	0 to 600 μM	22 nM	Tested in urine samples of athletes. Recovery range: 98.86% to 99.91%. RSD range: 3.56% to 4.41%	[121]
MWCNTs/SnO2–Zn2SnO4/CPE	Morphine ; Codeine	Morphine: 0.1–310 μM Codeine: 1–600 μM	Morphine: 0.009 μM Codeine: 0.009 μM	Morphine: Recovery 96.4–103.5% in human urine samples. Codeine: Recovery 97.0–100.3% in human urine and cough syrup samples.	[123]
MnFe2O4@CNT-N/GCE	Caffeine	1.0 × 10−6 to 1.1 × 10−3 M	3 0.83 × 10−6 M	–	[124]
SWNTs aptasensor	Cocaine	0.1–10 nM	105 pM	Detected cocaine spiked in rat serum with limit of detection of 136 pM	[125]
PANI-β-CD/fMWCNT/GCE	Cocaine	10–80 μM	1.02 μM	The sensor was used to analyze seized street samples of cocaine and showed good agreement with an HPLC reference method. Recoveries of 70-71% were obtained.	[126]
poly(MAA)/MWCNT/β-CD-GCE	Cocaine	12.2 to 200.0 μM	3.6 μM	The method was applied to determine COC in seized street samples and showed good accuracy compared to HPLC-DAD. Recoveries between 100.3–101.9% were obtained.	[127]

GOYAL et al. [¹²⁸] investigated the effect of the substrate material and the presence of metallic impurities in fullerene on its electrocatalytic activity for the detection of the nandrolone. They tested various substrate materials, including edge plane pyrolytic graphite electrode (EPPGE), indium tin oxide (ITO), GCE, gold electrode and basal plane pyrolytic graphite electrode. EPPGE gave the best performance, with the lowest oxidation potential and highest peak current for nandrolone detection. To study the role of metallic impurities in fullerene, they compared untreated fullerene with acid-purified and super-purified fullerene modified EPPGEs. Using an untreated fullerene modified EPPGE, they achieved a linear detection range of 0.01–50 nM nandrolone, with a sensitivity of 1.838 μA/nM, detection limit of 1.5 × 10^–11 M. Jalalvand and colleagues [¹¹¹] developed a novel dual template molecularly imprinted polymer (DTMIP) biosensor for the simultaneous detection of two anabolic steroids, nandrolone decanoate and testosterone decanoate. An ITO was modified with a composite of MWCNT, graphene, and an ionic liquid, onto which C60 fullerene was electrodeposited and reduced (Figure 10). The DTMIP film was then electrosynthesized using 4-aminobenzoic acid as the monomer and decanoate and testosterone decanoate as the templates. The biosensor showed overlapping voltammetric signals for decanoate and testosterone decanoate, so second-order calibration methods based on DPV data were used to enable simultaneous quantification. The parallel factor analysis 2 chemometric algorithm provided the best predictive performance for resolving the decanoate and testosterone decanoate signals.

Figure 10
Simultaneous biosensing of nandrolone and testosterone using DTMIP/C60/MWCNT-Gr-IL/ITO [¹¹¹].

Despite immense progress, widespread translation of carbon nanomaterial modified electrochemical sensors from laboratory prototypes to marketable devices needs surmounting of certain limitations. Mass production reproducibility of nanostructured electrode architectures may be restricted by batch-to-batch variability and scale-up synthesis challenges affecting sensor performance quality control. Contamination from metallic impurities poses interference issues needing extensive validations across diverse user cohorts accounting for age, gender and racial bias. Sample matrix effects arising from endogenous interfering molecules and protein fouling also impacts sensor longevity, detection accuracy/precision and reproducibility warranting surface functionalization optimization. Integration with microfluidics and multiplexing detection across arrays needs harmonization across target banned drug panels [¹²⁹,¹³⁰,¹³¹]. Nevertheless, carbon nanomaterial based electrochemical sensing offers a promising complementary technique to facilitate decentralized, rapid and convenient detection of major categories of doping agents and illicit drugs abused in sports.

7. CHALLENGES AND FUTURE PROSPECTS

Despite significant progress, widespread adoption of carbon nanomaterial-based electrochemical sensors for anti-doping analysis requires surmounting some inherent challenges. Figure 11 shows the mindmap of challenges and future prospects of carbon nanomaterials in electroanalysis for detection of illicit drugs in sports. Issues with reproducibility arising from varied synthesis protocols affects bulk production quality control and validation compliance. Lack of stability under harsh decontamination procedures, varying ionic strengths or extreme pH hampers field applicability necessitating surface functionalization refinements. Sensor longevity is also limited by fouling from proteins, lipids and metabolites demanding optimization of electrode coatings to minimize non-specific adsorption without compromising electron transfer efficiency. Miniaturized electronics and microfluidic integration also escalates per-sensor cost and power needs restricting affordability for routine usage.

Figure 11
Mindmap of challenges and future prospects of carbon nanomaterials in electroanalysis for detection of illicit drugs in sports.

The prospects for practical implementation can be enhanced by adopting green and sustainable protocols using biosources for controlled synthesis of composite carbon nanostructures. Improvements in Ambient ionization mass spectrometry allows simplified, reagentless and in situ characterization of surfaces to correlate nanoarchitecture-sensors function relationships guiding synthesis standardization. Use of better stabilizers, cross-linkers and capping agents need pursuance to prevent leaching, enhance connectivity and optimize uniformity. Exploring interfaces with redox polymers, functional nanotransducers and biomolecules will augment multiplexing capabilities, specificity and sensitivity. Electron beam and UV assisted surface grafting procedures need investigation to improve robustness for uninterrupted functioning over hundreds of cycles.

Efforts to develop integrated, miniaturized low power devices with wireless connectivity modules is vital to enable decentralized on-site analysis at point-of-care for routine doping control applications. Lab-on-PCB or origami paper-based microfluidic detectors with custom embedded electronics tuned using machine learning algorithms will facilitate automated sampling, sample preparation and rapid detection with data synchronization to central repositories for permanent record keeping. Commercialization potential also exists for smart wearable sweat monitors and ingestible sensors capable of long term tracking of exposure profiles towards chelation therapy and preventive interventions against illicit drug abuse in sports. Overall, the unique electrocatalytic properties of carbon nanomaterials undeniably demonstrate vast scope for engineering improved devices to curb use of performance enhancing banned substances and aid anti-doping enforcement efforts.

8. CONCLUSIONS

In summary, electrochemical sensors incorporating carbon nanomaterials such as graphene, carbon nanotubes and fullerenes demonstrate tremendous promise as rapid, sensitive and cost-effective analytical tools to complement chromatography-based verification methods for anti-doping analysis. Their exceptional electrocatalytic properties enable dramatic improvements in electron transfer kinetics, higher conductivity, larger surface area and better biocompatibility over traditional electrode materials. This augments limits of detection, selectivity even from complex biological matrices, analysis time and field-deployability vital for routine urine and blood screening of athletes. Graphene platforms in particular allow detection of stimulants like caffeine and cocaine down to micromolar or nanomolar levels compliant with anti-doping cut-offs. Covalent or non-covalent attachment of aptamers further adds molecular recognition capabilities while doping with metallic nanoparticles amplify signals via catalytic redox recycling. CNT nanoforests and threadlike RGO networks similarly detect opioid narcotics and enhance enzyme wiring for potential biosensing applications. While ongoing research aims to refine material properties and surface chemistry for improved stability, longevity and reproducibility, lab to field knowledge translation remains the next frontier. Integrating nanosensors with point-of-care microfluidic devices and on-site sampling kits aided by machine learning prediction models and wireless connectivity ­modules will facilitate decentralized testing capabilities. Progress towards low cost, wash-free and green synthesis protocols also merits unequivocal appraisal and validation across varied cohorts. Overall, fast and accurate carbon nanomaterial based electrochemical devices can serve as linchpins for anti-doping enforcement efforts through early screening, prevention of false negatives and targeted chelation therapy assisting future athletics integrity.

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Publication Dates

• Publication in this collection
  26 July 2024
• Date of issue
  2024

History

• Received
  14 Apr 2024
• Accepted
  27 May 2024