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leading to the formation of engineered cardiac tissues with stronger contraction capacity. The in vitro studies suggested that hybrid SWCNT/collagen hydrogels can be promising tissue sca olds for cardiac regeneration after myocardial arrest. In a similar line, a recent study described a biohybrid hydrogel prepared from hydrazidefunctionalized CNTs and solubilized pericardial matrix. This hydrogel is a suitable environment for maturation of human-induced pluripotent stem cell-derived cardiomyocytes, constituting a promising material for stem cell-based cardiac tissue engineering [209].

4.4.3  CNTs and Stem Cells

Stem cells (SC) have attracted the attention of researchers around the world during the last decade due to their ability to self-renew and di erentiate, depicting multiple potential applications for tissue engineering and regenerative medicine. CNTs presented excellent properties as culture substrate [210], having the ability to dynamically direct the SC lineage, modulating proliferation and di erentiation of various types of SC. Di erent studies have reported the improvements achieved by growing SC in CNT-based nanocomposites. These materials were able to promote di erentiation of mouse neural SC to neurons and oligodendrocytes [211], neural di erentiation of human embryonic stem cells [212], and di erentiation of human mesenchymal stem cells [213], among others.

4.5 Other Applications

The versatility of carbon nanotubes in biomedicine and preclinical setup is very large, with many studies reporting the use of CNTs to solve the problem under investigation. Carbon nanotubes are being used, for example, to construct brain electrodes [214], or as biosensors for bone cells [215] or the infuenza virus [112]. By linking CNTs to antigenic peptides, they could improve the major hurdles associated with vaccine delivery [216]. In fact, they can act as excellent vaccine carrier systems having a great potential to stimulate the innate immune response. Also, the combination of CNTs with antibiotics could help to overcome the growing problem of antibiotics resistance [190]. When properly functionalized, CNTs can also be used in antiviral drug delivery [217].

5 Conclusions

Bionanotechnology is a new promising tool for improving the management of numerous pathologies. A wide range of nanomaterials have been prepared, characterized, and evaluated for numerous biomedical applications to solve specific problems not achievable with classical approaches. Among them, carbon nanotubes present unique features and physical, chemical, and biological properties. These intrinsic attributes can be notably improved though coating, surface functionalization, and decoration with di erent molecules, ligands, or nanostructures. All of

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these turn CNTs into ideal platforms with diagnostic, therapeutic, and theranostic possibilities not accessible for other nanoparticles and with promising preclinical and clinical applications.

In this review, the biomedical applications of CNTs have been addressed in different fields of drug and/or gene delivery, bioimaging, and tissue engineering. The special electronic and mechanical qualities of nanotubes make them suitable for theranostic applications as providing an exceptional platform for combining disease detection and treatment capacity at the same time. These structures can be used in diagnosis as e cient biosensors or contrast agent for non-invasive imaging, and at the same time, increase the lifetime of drugs in organism and facilitate their direct delivery within cells of a target-specific tissue. Also, nanotubes have reached a vital relevance in biotechnology, being an excellent sca old on their own or taking the part of hybrid materials for regenerative medicine. They have proved to be useful in cell growth and proliferation, enabling the engineering of di erent tissues. The studies included in this review have highlighted the potential of CNTs and justified all the e orts in optimizing their use as an alternative therapy for complicated medical conditions with no current treatments.

Nevertheless, despite the numerous and intensive studies, some important inconveniences, which preclude potential clinical applications, need to be overcome, with toxicity probably being the most important handicap. The triad of CNTs functionalization, type, size, and purity have been identified as leading causes determining the utility of nanotube-based complex in vivo. Collating reliable cellular and animal data with respect to molecularly well-defined architectures provides a basis for further breakthroughs on the horizon.

Acknowledgements  This study was funded by grants from the Ministry of Economy, Industry and Competitivity (SAF2017-83043-R), and by the Program MULTITARGET&VIEW-CM from Community of Madrid, Spain (S2017/BMD-3688), involving contributions from FEDER and FSE funds.

Authors Contributions  Pilar López-Larrubia had the idea for the article. Viviana Negri, Jesús PachecoTorres, Daniel Calle, and Pilar Lopez-Larrubia performed the literature search and data analysis, drafted and critically revised the work.

Compliance with Ethical Standards 

Confict of interest  The authors declare that they have no conficts of interest.

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Afliations

Viviana Negri1 · Jesús Pacheco Torres2 · Daniel Calle3 · Pilar López Larrubia4

1\ Departamento de Biotecnología y Farmacia, Facultad de Ciencias Biomédicas, Universidad Europea de Madrid, Villaviciosa de Odón, Spain

2\ Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

3\ Laboratorio de Imagen Médica, Hospital Universitario Gregorio Marañón, c/Dr. Esquerdo 56, 28007 Madrid, Spain

4\ Instituto de Investigaciones Biomédicas “Alberto Sols”, CSIC-UAM, c/Arturo Duperier 4, 28029 Madrid, Spain

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