# Heavy Metal Ion Detection Platforms Based on a Glutathione Probe: A Mini Review
## 1 Introduction  
In general, heavy metals are the metals with relatively high mass densities (above 5 g/cm\({}^{3}\)), such as platinum, gold, mercury, and lead. The definition of heavy metals varies from discipline to discipline due to different concerns and perspectives. For physiology and pathology, heavy metals mainly refer to heavy elements with obvious biotoxicity. In terms of toxicity, the most common heavy metals include lead (Pb), mercury (Hg), arsenic (As), cadmium (Cd), and chromium (Cr) [1; 2; 3; 4]. These heavy metal ions (HMIs) accumulate in the human body and cause chronic poisoning, resulting in damage to the immune, gastrointestinal, reproductive, and nervous systems [5; 6; 7]. Long-term exposure to heavy metals may even cause cancer in humans [8]. Being non-biodegradable, HMIs will continue to exist for decades and even hundreds of years if they are released into the environment [9]. With increasing human activities in mining and manufacturing, etc., HMI contamination and pollution pose great risks to ecological and human health [10; 11]. Therefore, it is of great importance to be able to effectively screen for and quantitatively determine HMIs in a range of situations, including food safety, environmental pollution, and clinical diagnosis. Many international organizations and regulatorybodies, such as the World Health Organization (WHO) and the U.S. Environmental Protection Agency (EPA), have listed heavy metals as priority substances for intensive monitoring [1]. In practice, most countries have set standards on the permissible limits for HMI concentrations in water or other mediums to protect the environment and public health. Traditional HMI measurements are mostly performed using spectroscopic techniques, including atomic absorption spectroscopy (AAS) [4; 12], X-ray fluorescence spectrometry (XRF) [4; 13], and inductively coupled plasma mass spectrometry (ICP-MS) [4; 14], which are gold standards in HMI detection. However, they are expensive, difficult to perform, require complicated pretreatment for the samples, and need to be operated in a central laboratory setting. Thus, traditional spectroscopic techniques cannot meet the needs for pervasive HMI monitoring and screening. In contrast, surface-based biosensors are a good candidate to realize low-cost, sensitive HMI detection with a quick turn-around time. Similar to other biochemical sensors, there are three important components in an HMI sensor: analyte recognition, physical support for probe immobilization, and signal transduction. Various types of sensors have been reported, including nanoparticles [15; 16; 17], field effect transistors (FETs) [18; 19; 20], and working electrodes for voltammetric analysis [21]. In terms of signal transduction, there are mainly optical [15] and electrochemical methods [4]. Specific target recognition is always critically important to analyte detection. Antibody [22], nuclei acids [23; 24], and peptide/amino acids [25; 26] are the most commonly used probes to recognize and bind with HMIs. An antibody as a probe has the best specificity, but faces challenges when detecting HMIs. HMIs are too small to be directly detected with good sensitivity by an antibody, and antibody binding reactions may require a fluid environment different from that HMIs naturally exist in. Two types of functional nuclei acid probes have been developed for metal sensing: aptamers and DNAzymes. It is well-known that screening aptamer sequences to find one that specifically binds with a certain HMI is difficult, in addition to being laborious and time-consuming. Very few metal ions have successfully found their specific aptamers [27; 28]. DNAzymes can selectively detect HMIs based on their catalytic activity; however, another nuclei acid sequence is required to be added to work as the substrate-enzyme pair. During metal detection by DNAzyme, additional steps and time are needed to allow for catalytic reactions between the DNAzyme and the substrate.