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4  Biomedical Applications of Carbon Nanotubes

As we anticipated in the previous sections, CNTs present some physical features very interesting for biomedical applications, including a large surface area [130], electrical [23] and thermal conductivity [131], and optimal mechanical properties [132]. Some of these applications are achievable through the CNT’s conjugation with di erent biomolecules or compounds like polymers, proteins, DNA and RNA, among others, as above described (Fig. 7). Besides, their needle shape permits them to cross biological membranes and access cells and tissues in a non-a ordable way for most of the common drugs and compounds. Nevertheless, some challenges need to be overtaken to boost their potential in biomedicine. These include low biocompatibility [133], mainly due to poor water solubility, low dispersivity, and high toxicity [47]. Even so, numerous groups have reported di erent and very interesting applications for CNTs also in the preclinical and in the clinical settings.

4.1 Diagnostic applications

Early diagnosis and proper monitoring of disease is vital for e cient treatment of illnesses. This encourages the development of improved methodologies that solve some of the inconveniences and handicaps of the current methods, including sensitivity and selectivity, spatial and temporal resolution, cost, etc. The use of nanoparticles in general, and carbon nanotubes in particular, o ers a wide range of possibilities that could be key in achieving these improvements.

4.1.1 Biosensors

Biosensors are devices incorporating biological elements with unique binding specificities towards target analytes. In this field, CNT’s characteristics make them very interesting to investigate as relevant constituents of electrochemical biosensors [135]. Nanotubes are well suited for transduction of electric signals generated

Fig. 7  Schematic representation of surface functionalization and loading of carbon nanotubes for biomedical applications (with permission from Fernandes et al. [134])

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upon recognition of a target, so, numerous applications are reporting the design of nanotube-based biosensors to detect and monitor di erent pathologies [136, 137]. Recently, a three-dimensional network of carbon nanotubes on Si pillar substrate has been developed for the accurate detection of oral squamous cell carcinoma in clinical saliva samples [138]. In this work, Song and colleagues described the preparation of the sensor, the in vitro characterization, and the clinical applicability. The results obtained with this new CNT network showed a good correlation with data obtained using the commercially available electrochemiluminescence detection system employed in the hospital. Also, a novel CNT-based biosensor has been used for ultrasensitive detection of hydrogen peroxide and glucose in human serum, with a great interest for basic research and disease diagnosis [139]. In this study, the authors constructed a ratiometric fuorescent nanosensor based on the peroxidaselike properties of a hierarchical cobalt/carbon nanotube hybrid nanocomplex. This system assay developed reaches a detection limit of H­2O2 of 100 nM and a selective and sensitive detection of glucose as low as 150 nM. In a di erent approach, multivalent electrodes for glucose biosensing were constructed through multiple functionalization of CNTs [140]. Three di erent pyrene derivatives were simultaneously immobilized on the nanotube surface by – -stacking: adamantane-pyrene, biotinpyrene, and nitrilotriacetic. They were adsorbed on the nanotube sidewalls to allow the step-by-step immobilization, via supramolecular host–guest interactions, of β-cyclodextrin modified glucose oxidase, biotinylated glucose oxidase, and histidine modified glucose (Fig. 8). The calibration curves for the glucose responses were performed by amperometry and using glucose oxidase as an enzyme model for all immobilization steps.

DNA detection is a very active research area holding great promise in the early detection of many diseases and pathological processes, and CNTs o er strong opportunities to achieve that [141]. An interesting study reported the synthesis of a multi-functional gold/iron-oxide nanoparticle-CNT as a virus DNA-sensing platform [142]. The authors prepared the sensor through a simple two-step method obtaining the hybrid nanostructure that exhibited excellent detection potential and DNA sensing performance for di erent diseases. Chen and collogues also reported the fabrication of a DNA nano-biosensor system containing carbon nanotubes to detect the presence of Mycobacterium tuberculosis rapidly and with a great sensitivity [143]. CNTs have also been experimentally and theoretically investigated as conducting channels in a chemiresistor for the electrochemical detection of doublestranded DNA [144]. More recently, the development of a CNT-based field-e ect transistor for DNA hybridization detection was reported [145]. In this sensor, DNA can bind well to a suspended CNT, avoiding the adverse e ects of a substrate on a sensing material, and reaching a detection limit up to 10 aM.

4.1.2 Imaging

Carbon nanotubes can be powerful tools with diagnosis purposes not only as biosensors but also to be used in imaging technologies. Due to their excellent intrinsic properties, CNTs have been employed as CAs in photoimaging techniques and are good platforms to carry molecules that make them detectable with di erent imaging

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Fig. 8  SWCNT multivalent glucose biosensor by a coating process with adamantane-pyrene, biotin-pyr- ene and nitrilotriacetic acid-pyrene, and further host–guest interaction with avidin and β-cyclodextrin

modalities, as positron emission tomography (PET) or magnetic resonance imaging, among others [146].

MRI is probably the most powerful and versatile of all imaging techniques used in the clinical routine, biomedical research, and preclinical studies. Among its advantages, MRI presents wide implementation, high cost e ciency, non-invasive- ness, and it does not use ionizing radiation. Although this imaging technique o ers a great contrast between pathological and healthy tissues, the use of contrast agents is often required. CNTs are highly explored as CA candidates, with great sensitivity and specificity, low dose and reduced side e ects, with numerous in vitro and in vivo studies reported in the literature [147]. The most direct approach is to use them as negative T2 CAs making use of the remaining metal catalyst employed in the synthesis of CNTs [148], but these structures can be also prepared as positive T1 contrast media either by addition or trapping of gadolinium (Gd) complex [149, 150]. In both situations, some issues have to be solved to boost their widespread use, like toxicity and dispersion capacity [34]. Despite this, CNT-based CA are promising for cell labeling and MRI tracking, being of great interest on stem cell-based therapies that have emerged as a promising approach for the treatment of di erent diseases. With this aim, Moghaddam et al. developed a method to coat the surface of gado-nanotubes (GNTs) with Gd and polyacrylic acid polymer generating a powerful MRI T1 contrast agent, with an extremely short T1 relaxation and an improved dispersibility in water without the need of surfactants [151]. The authors used these

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