Carbon nanotubes as optical biomedical sensors☆
Graphical abstract
Introduction
Biosensors have an important impact on basic scientific research and healthcare. In this area, scientific breakthroughs are often facilitated by new sensing technologies that enable investigation of unstudied biological phenomena. In healthcare, new diagnostic tools are needed to improve clinical treatments. Moreover, many challenges of the healthcare-system can only be solved by new sensor technology such as point-of care sensor devices. Therefore, biosensors will become even more important in the future. Biosensor development is catalyzed by the discovery of new materials, and in the last decade, a great amount of work has been dedicated to develop nanomaterial-based biosensors [1], [2], [3], [4], [5], [6], [7], [8], [9].
Materials like nanoparticles [10], quantum dots [1], nanowires [2], graphene [3], graphene quantum dots [4] or carbon nanotubes [5], [6], [7], [8], [9] have shown their potential in the fabrication of highly sensitive and selective biosensors. An intriguing example for new approaches, which were impossible without these new materials is carbon-nanotube endoscopes, which have been used to probe the interior of living cells [11]. In the future, these approaches could be useful to transduce electrochemical information from inside the cell to the outside.
This example illustrates how the nanoscale size of a sensing element might improve sensor performance or enhance spatial resolution. In many cases, a biological application would only be possible if the sensing element has the same size (i.e. nm) or a smaller size than the biological structures. Single cells or even organelles could only be probed without major perturbations if the sensor had such small dimensions.
Low-dimensional materials do not only provide a new length scale. These materials have electrons and phonons that are confined in fewer than three dimensions leading to unique physical and chemical properties that can be used for sensing applications. Using such properties it was possible to detect complementary nucleotide sequences with extremely high sensitivities in the femtomolar-range [12] or the cancer marker PSA (prostate specific antigen) in the attomolar-range [13].
Among the different kinds of nanomaterials carbon nanotubes are especially promising building blocks for biosensor design. The electrical detection of chemical solvent vapors [14] was one of the first examples of highly sensitive carbon nanotube-based sensors. More recently, an electrical sensor was developed that could identify fruit ripeness by measuring ethylene gas concentrations [15]. In the biomedical field, pioneering work on optical sensors for glucose detection [16] or DNA polymorphisms [17] has been conducted. In some cases carbon nanotubes have also been used to enhance the sensitivity of classical biosensors. For example, carbon fiber microelectrodes are used to measure neurotransmitter concentrations by cyclic voltammetry (CV). Recently, carbon nanotube coated carbon fiber microelectrodes showed enhanced sensitivity and selectivity [18].
All the aforementioned examples show that there is a plethora of distinct applications for biosensors, and that nanomaterials like carbon nanotubes can add or create beneficial properties. But what are the most important design principles and what are the most challenging problems for biosensor design? To understand this fundamental question the definition of a (bio)sensor is a good starting point.
A sensor is a device that detects a chemical, physical or biological quantity and transduces it into a signal. Biosensors are sensors that detect such quantities in a biological environment. In most of the cases biosensors are used to detect a certain biologically relevant analyte. Every sensor has to be composed of at least two units: 1) A recognition unit that provides a selective interaction with the analyte and 2) a transduction unit that converts the recognition event into a signal that can be directly observed.
This definition immediately serves as a guide for biosensor design. A sensor is usually built by combining a recognition unit such as antibodies, aptamers, DNA-sequences or lectins and a signal transduction mechanism/material. The analytes can be detected by a molecular recognition event but also by other physico-chemical properties. One prominent example is the electrochemical dopamine detection with carbon fiber electrodes by utilizing its redox chemistry. By using such electrodes, basal and transient levels of dopamine in the brain were measured [19].
In combination with the signal transduction mechanism the recognition element is the reason for high sensitivity of the sensor. However, especially in biological environments the selectivity of the sensor is of similar or even higher importance. For example, detection of rare biomolecular species in blood is hindered by non-specific protein adsorption to nanoparticle sensors [20]. Useful methods to circumvent non-specific protein adsorption involve surface passivation, which renders the surface inert to unspecific adsorption of molecules [21].
To date, there are several excellent reviews on electrical, electrochemical and field-effect transistor (FET) based carbon nanotube biosensors [5], [22], [23], [24], [25], [26], [27], [28], [29]. In this review article we will focus on the emerging area of optical carbon nanotube based biosensors [6], [9]. First, we will introduce the basic physical and chemical properties of carbon nanotubes that are important for biosensor design. Then we will review recent advances. The different sections are classified into important biomolecule subgroups. Finally, we will summarize the current status of these sensors and identify the most challenging technical and biological problems for the future.
Section snippets
Carbon nanotubes
Until the 1980s only three carbon allotropes were known: graphite, amorphous carbon and diamond. Since then, the discovery, characterization and isolation of three additional carbon allotropes (fullerenes [30], carbon nanotubes [31] and graphene [32]) have fueled the advancement of a major field of science.
Carbon nanotubes have attracted a lot of basic research efforts because of their unique physical and chemical properties. The interest in carbon nanotubes has even increased due to possible
DNA detection
The ability to detect changes in DNA sequence and structure may prove useful for applications in personalized medicine [87]. For example, single nucleotide polymorphisms (SNPs) are one of the most common types of genetic mutation, and can lead to a variety of autoimmune diseases [88], or the development of cancer [89], [90], among others. It has been demonstrated that DNA-wrapped SWCNTs can directly detect SNPs by examining hybridization kinetics between the SWCNT-bound sequence, and a
Adenosine 5′-triphosphate (ATP)
Adenosine 5′-triphosphate (ATP) is used as a universal energy storage molecule in all organisms. Therefore, the ability to spatially detect ATP is useful for understanding a variety of cellular processes, ranging from ion-channel regulation [99] to intercellular signaling cascades [100]. To date, several approaches for ATP detection have been described, either based on electrochemical [101] or spectroscopic methods including bioluminescence [102], [103], [104], [105], [106], fluorescence [107],
Protein and biomarker detection
Protein biomarkers are specific proteins, either circulating in body fluid, or displayed on cell surfaces, which are indicative of diseased states. The research area of biomarker detection focuses on rapid, sensitive detection of known biomarkers in order to diagnose diseases in a timely and accurate fashion. Methods for biomarker detection can be divided into two separate categories: those, which are label-based, and those, which are label-free. Label-based methods require the labeling of
Glucose detection
Diabetes mellitus is a severe disease and continuous monitoring of glucose levels is critical for its treatment [154], [155]. For this reason glucose detection has become a major task for biosensor development.
Although nanomaterials have aided in the sensitivity, efficiency and size of glucose monitors, electrochemical sensors still suffer from the need for relatively invasive sampling means such as transcutaneous electrode placement or direct blood withdrawal. As such, a great deal of
Glycoprofiling
Glycans, or surface carbohydrates, coat every cell and many proteins in the human body. They act as identification tags for differentiation, signaling, and transport. Thus glycans play a pivotal role in human health and disease. Glycans, unlike proteins and nucleic acids, are more structurally diverse due to monosaccharide building blocks that have multiple, anomeric linkage sites. This gives rise to branched oligosaccharides that are difficult to characterize. The established procedure to
Conclusions and outlook
Carbon nanotubes are becoming a promising building block for biosensor technology. Although the first biosensors with integrated carbon nanotubes were electrical or FET sensors, in the past few years several examples of optical carbon nanotube based sensors were demonstrated. An optical signal transduction has intrinsic advantages compared to electrical transduction such as contactless signal transduction or simple up scaling and multiplexing of surface assays. In this review article we
Acknowledgment
S.K. was supported by a fellowship from the Deutsche Forschungsgemeinschaft (DFG). M.S.S. is grateful for a grant from the National Science Foundation, as well as funding from the Novartis and Sanofi Aventis. N.F.R. is appreciative of a National Science Foundation Graduate Research Fellowship. A.J.H. acknowledges funding from the DOE SCGF program, made possible in part by the American Recovery and Reinvestment Act of 2009, administered by ORISE-ORAU under contract no. DE-AC05-06OR23100.
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This review is part of the Advanced Drug Delivery Reviews theme issue on “Carbon nanotubes in medicine and biology - Therapy and diagnostics".