Elsevier

Biomaterials

Volume 28, Issue 2, January 2007, Pages 344-353
Biomaterials

Review
Carbon nanotube applications for tissue engineering

https://doi.org/10.1016/j.biomaterials.2006.07.044Get rights and content

Abstract

As the field of tissue engineering advances, new tools for better monitoring and evaluating of engineered tissues along with new biomaterials to direct tissue growth are needed. Carbon nanotubes may be an important tissue engineering material for improved tracking of cells, sensing of microenvironments, delivering of transfection agents, and scaffolding for incorporating with the host's body. Using carbon nanotubes for optical, magnetic resonance and radiotracer contrast agents would provide better means of evaluating tissue formation. In addition, monitoring and altering intra and intercellular processes would be useful for design of better engineered tissues. Carbon nanotubes can also be incorporated into scaffolds providing structural reinforcement as well as imparting novel properties such as electrical conductivity into the scaffolds may aid in directing cell growth. Potential cytotoxic effects associated with carbon nanotubes may be mitigated by chemically functionalizing the surface. Overall, carbon nanotubes may play an integral role as unique biomaterial for creating and monitoring engineered tissue.

Introduction

The goal of tissue engineering is to replace diseased or damaged tissue with biologic substitutes that can restore and maintain normal function. Major advances in the areas of cell and organ transplantation, as well as advances in materials science and engineering, have aided in the continuing development of tissue engineering and regenerative medicine. As the field of tissue engineering advances, there is a growing need for better monitoring and evaluating tools of engineered tissues along with new biomaterials to facilitate tissue growth. Like tissue engineering, which involves directing the growth of cells to form higher ordered structures, nanotechnology is also a bottom-up approach that focuses on assembling simple elements to form complex structures. Nanotechnology involves utilizing materials which possess at least one physical dimension between 1 and 100 nm to construct structures, devices, and systems that have novel properties. In fact, many biological components, such as DNA, involve some aspect of nano-dimensionality.

The nano-dimensionality of nature has logically given rise to the interest in using nanomaterials for tissue engineering. These materials have the potential to have a significant impact on tissue engineering. Already, iron oxide superparamagnetic nanoparticles and quantum dots have been used to track the biodistribution of cells [1], [2]. Interestingly, nanomaterials can also be multifunctional capable of both targeting and imaging [3]. One nanomaterial that has the potential for multiple uses in tissue engineering is the carbon nanotube.

Following the discovery of carbon nanotubes by lijima [4], carbon-based nanotechnology has been rapidly developing as a platform technology for a variety of uses including biomedical applications. Carbon nanotubes are cylindrical carbon tubes possessing nanometer diameters with much longer lengths (>100 nm) resulting in very large aspect ratios (Fig. 1). They possess a very broad range of electronic, thermal, and structural properties defined by diameter, length, and chirality or twist. Carbon nanotubes can be composed of a single tube—commonly called a single-walled carbon nanotube (SWNT)—or concentric cylinders of carbon—commonly referred to as multi-walled carbon nanotubes (MWNTs).

Carbon nanotubes are generally prepared via three methods: arc-discharge [5], laser ablation [6], and chemical vapor deposition (CVD) [7]. CVD is the most widely used commercial method of producing carbon nanotubes. This process typically involves reacting a metal catalyst with a hydrocarbon feedstock at high temperatures (>700 °C) to produce carbon nanotubes which depending on the reaction conditions can create a wide variety of lengths (nanometers to millimeters) and widths (1–100 nm). Nanotubes produced using this method commonly have metal catalysts or carboneous deposits on the outside of the nanotube. Since metal catalysts such as nickel can be used for growing carbon nanotubes, there is concern about carbon nanotubes being cytotoxic. Thus a purification step is usually required before carbon nanotubes can be used for biomedical applications.

There are several approaches to purifying carbon nanotubes [8], [9], [10], [11]. Refluxing carbon nanotubes in an oxidizing acid such as nitric acid is one of the most popular methods of purification. This process oxidizes and removes the metal catalysts and carboneous deposits from the inside and outside of the tube. In addition, acids can attack the more reactive ends of the carbon nanotubes opening the tube ends and creating carboxylic acid groups. In addition, any defects in the tube may also be oxidized creating additional carboxylic acids groups along the length of the tube. These carboxylic acid groups can be further functionalized allowing tuning of the surface chemistry of the nanotube.

With its carbon composition, high aspect ratio, electrical and physical properties, there has been growing interest in using carbon nanotubes for biomedical applications. Since the year 2000, there has been an approximate doubling each year of articles related to carbon nanotubes for use in biomedical applications with 2004 marking the beginning of applying carbon nanotubes to tissue engineering (Fig. 2). This review focuses on research involving carbon nanotubes which are relevant to the tissue engineering field. There are four areas that carbon nanotubes can be used in which are relevant for tissue engineering—cell tracking and labeling, sensing cellular behavior, augmenting cellular behavior and enhancing tissue matrices.

Section snippets

Cell tracking and labeling

The ability to track implanted cells, and to monitor the progress of tissue formation in vivo and non-invasively is important especially in tissue-engineered constructs of clinically relevant sizes. Labeling implanted cells would not only help in evaluating the viability of the engineered tissue but would also help in understanding of the biodistribution and migration pathways of transplanted cells. Non-invasive methods are particularly attractive because traditional methods such as intravital

Sensing cellular behavior

While tracking cells aids in understanding cell migration, monitoring the cellular microenvironment would provide even more knowledge needed for successfully engineering tissue. The ability to monitor cellular physiology such as ion transport, enzyme/cofactor interactions, protein and metabolite secretion and cellular behavior such as matrix adhesion could help design better engineered tissues. Nanosensors could be used to provide continuous monitoring of the performance of the engineered

Augmenting cellular behavior

A third area where carbon nanotubes can make an impact in tissue engineering is controlling the production of or delivery of tissue-inducing substances such as growth factors. Carbon nanotubes have already been used for a number of cell altering applications including localized drug delivery [37] and transfection [28]. They have also been proposed as ion channel blockers [38]. Many of these methods take advantage of the large aspect ratio and ease of functionalization of carbon nanotubes. Thus,

Matrix enhancement

A fourth area that carbon nanotubes will impact tissue engineering is for structural support. The matrix plays a critical role in tissue engineering. It is responsible for defining the space the engineered tissue occupies and aiding the process of tissue development. While popular synthetic polymers such as PLGA and PLA have been used for tissue engineering, they lack the necessary mechanical strength. In addition, such polymers cannot easily be functionalized in contrast to carbon nanotubes

Cytotoxicity

However promising a new technology or material might be for biomedical applications, it must be safe. Any time a foreign substance is introduced into the body, understanding the organism's response to it is crucial. There is debate in the literature regarding the cytotoxicity of fullerene nanomaterials such as buckyballs and carbon nanotubes. Thus a review would not be complete without reviewing the cytotoxicity of carbon nanotubes. Some studies have indicated that carbon nanotubes are

Conclusions and future outlook

Carbon nanotubes appear well suited as a biomaterial and may become a useful tool for tissue engineering. Carbon nanotubes have the capacity to be used in cellular imaging, chemical and biological sensing, bioactive agent delivery, and matrix engineering. While new uses of carbon nanotubes for biomedical applications are being developed concerns about cytotoxicity may be mitigated by chemical fuctionalization. However, there will be some limitations to this nanomaterial since it is not

References (65)

  • X.H. Gao et al.

    In vivo cancer targeting and imaging with semiconductor quantum dots

    Nat Biotechnol

    (2004)
  • S. Iijima

    Helical microtubules of graphitic carbon

    Nature

    (1991)
  • C. Journet et al.

    Large-scale production of single-walled carbon nanotubes by the electric-arc technique

    Nature

    (1997)
  • A. Thess et al.

    Crystalline ropes of metallic carbon nanotubes

    Science

    (1996)
  • A.M. Cassell et al.

    Large scale CVD synthesis of single-walled carbon nanotubes

    J Phys Chem B

    (1999)
  • A.C. Dillon et al.

    A simple and complete purification of single-walled carbon nanotube materials

    Adv Mater

    (1999)
  • P. Cherukuri et al.

    Near-infrared fluorescence microscopy of single-walled carbon nanotubes in phagocytic cells

    J Am Chem Soc

    (2004)
  • D.A. Heller et al.

    Single-walled carbon nanotube spectroscopy in live cells: towards long-term labels and optical sensors

    Adv Mater

    (2005)
  • D.L. Shi et al.

    Luminescent carbon nanotubes by surface functionalization

    Adv Mater

    (2006)
  • A.K. Guptaa et al.

    Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications

    Biomaterials

    (2005)
  • S. Mornet et al.

    Magnetic nanoparticle design for medical diagnosis and therapy

    J Mater Chem

    (2004)
  • B. Ballou et al.

    Noninvasive imaging of quantum dots in mice

    Bioconjugate Chem

    (2004)
  • R.D. Bolskar et al.

    First soluble M@C60 derivatives provide enhanced access to metallofullerenes and permit in vivo evaluation of Gd@C60[C(COOH)2]10 as a MRI contrast agent

    J Am Chem Soc

    (2003)
  • E. Toth et al.

    Water-soluble gadofullerenes: toward high-relaxivity, pH-responsive MRI contrast agents

    J Am Chem Soc

    (2005)
  • B. Sitharaman et al.

    Superparamagnetic gadonanotubes are high-performance MRI contrast agents

    Chem Commun

    (2005)
  • R. Singh et al.

    Tissue biodistribution and blood clearance rates of intravenously administered carbon nanotube radiotracers

    Proc Natl Acad Sci USA

    (2006)
  • M.C. Denis et al.

    Imaging inflammation of the pancreatic islets in type 1 diabetes

    Proc Natl Acad Sci USA

    (2004)
  • H. Jung et al.

    Detection of apoptosis using the C2A domain of synaptotagmin I

    Bioconjugate Chem

    (2004)
  • M. Zhao et al.

    Non-invasive detection of apoptosis using magnetic resonance imaging and a targeted contrast agent

    Nat Med

    (2001)
  • E.A. Schellenberger et al.

    Surface-functionalized nanoparticle library yields probes for apoptotic cells

    Chem Bio Chem

    (2004)
  • P.M. Winter et al.

    Molecular imaging of angiogenesis in early-stage atherosclerosis with alpha(v)beta(3)-integrin-targeted nanoparticles

    Circulation

    (2003)
  • A.H. Schmieder et al.

    Molecular MR imaging of melanoma angiogenesis with alpha(nu)beta(3)-targeted paramagnetic nanoparticles

    Magnet Reson Med

    (2005)
  • Cited by (0)

    View full text