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Posted: May 24, 2011

Graphene used in biomedical applications can control the fate of stem cells

(Nanowerk Spotlight) It is widely believed that stem cell therapies have the potential to revolutionize the treatment of human diseases. The range of potentially ground-breaking therapies based on stem cells ranges from combating Alzheimer's Disease to regenerative medicine (see: "Nanotechnology based stem cell therapies for damaged heart muscles").
Key to the success of such therapies are two crucial properties: the ability of stem cells to develop into any specialized cell type depending on the specific need at hand; and the ability to guide the fate of the stem cells by various external factors. The latter is usually achieved by the proper engineering of their micro environment and the concurrent administration of specific 'protein cocktails', generally referred to as biochemical inducers or growth factors. Using these techniques, current tissue engineering approaches for example combine different scaffold materials with living cells to provide biological substitutes that can repair and eventually improve tissue functions.
The downside of guiding cells towards specific cells types with such biochemical inducers is that they need to be administered over longer periods of times (several weeks) repetitively (every few days). Another drawback is that such a therapy introduces a number of chemicals and proteins into the body whose influence is not yet fully understood. A final consideration: such biochemical inducers are rather costly. And then there always is the possibility that artificial substrates are rejected by the body's immune system.
Researchers in Asia have now demonstrated that graphene provides a promising biocompatible scaffold that does not hamper the proliferation of human mesenchymal stem cells (hMSCs) and accelerates their specific differentiation into bone cells. The differentiation rate is comparable to the one achieved with common growth factors, demonstrating graphene's potential for stem cell research.
>Graphene accelerates osteogenic differentiation
Graphene accelerates osteogenic differentiation. (a) Optical image of 1 cm x 1 cm, partially graphene-coated Si/SiO2 chip, showing the graphene boundary. (b) Osteocalcin (OCN) marker showing bone cell formation on the same chip only on the graphene-coated area; the graphene boundary is also clearly visible here. (c,d) Alizarin red quantification deriving from hMSCs grown for 15 days on substrates with/without graphene. (c) Cells grown in the absence of BMP-2. Control with coverslips is shown as a reference. (d) Cells grown in the presence of BMP-2. Conventional plain coverslips were used as a positive control. (e-h) PET substrate stained with alizarin red showing calcium deposits due to osteogenesis. (e) PET without BMP-2 and without graphene; (f) PET without BMP-2 and with graphene; (g) PET with BMP-2 and without graphene; (h) PET with both BMP-2 and graphene. Scale bars are 100 µm. (Reprinted with permission from American Chemical Society)
Graphene is only recently finding its way into biomedical applications. Most of the recent work in this area focuses on using graphene as a biosensor, i.e. as a passive medium, which monitors some external stimulus, usually by taking advantage of the fact that graphene's resistance depends strongly on nearby electric fields and signals (see for instance: "Graphene-DNA biosensor selective, simple to create"). But this is from a fundamental point of view nothing new; silicon wires, diamond films and carbon nanotubes all have been already used for this type of application.
"In our work, we show that graphene can be used in a more active way in biomedical applications, i.e. it can control the fate of a stem cell," Barbaros Özyilmaz, an assistant professor in the Department of Physics at National University of Singapore (NUS), explains to Nanowerk. "The reason why this actually happens is not clear, but it is almost certainly due to a mix of the many outstanding and unique properties of the graphene sheet, i.e. its 2D nature, its mechanical, chemical and electrical properties."
Özyilmaz points out that the downside of this lack of understanding is that it is hard to pinpoint why exactly the use of graphene leads to stem cell differentiation. "But we are working on understanding this now in more detail. My group recently got a US$500k grant to study the graphene cell interface – this is not directly related to the stem cell work, but is meant to create a combined AFM-optical-electrical characterization set-up uniquely for understanding how the cell exerts a force on graphene and vice versa."
Reporting their findings in a recent issue of ACS Nano ("Graphene for Controlled and Accelerated Osteogenic Differentiation of Human Mesenchymal Stem Cells"), a NUS team working with collaborators from Sungkyunkwan University in South Korea, show that graphene provides a new type of biocompatible scaffold for stem cells.
In their experiments, the researchers studied the influence of graphene on stem cell growth by investigating four substrates with widely varying stiffness and surface roughness: polydimethylsiloxane (PDMS); polyethylene terephthalate (PET); glass slide; and silicon wafer with 300 nm silicon dioxide. They performed two distinct sets of experiments: First, cell viability was studied with cells cultured in normal stem cell medium. Next, stem cell differentiation was examined in cells cultured on conventional osteogenic media.
The team's motivation was to go beyond related experiments that were performed with carbon nanotubes. However, carbon nanotubes need to be functionalized, they come in a number of different forms and chirality, and from a practical point of view it is not clear how safe such they are. Maybe most importantly, it would be difficult to fully cover a surface with carbon nanotubes and use them as coating material which can simultaneously act as a barrier.
"In fact" recounts Özyilmaz, "my collaborator Giorgia Pastorin was already studying carbon nanotubes in stem cell related applications and discussions with her let us both realize that graphene could help address many of the open questions related to carbon nanotubes."
"We found that that graphene does not hamper the normal growth of stem cells and that the incorporation of this material in implants or injured tissues would not affect the physiological conditions of the microenvironment" notes Özyilmaz. "We also could demonstrate in our experiment that graphene is the driving force of bone cell formation, regardless of the underlying substrate."
"Remarkably, graphene accelerates cell differentiation even in the absence of commonly used additional growth factors such as BMP-2" says Özyilmaz. "Taking into consideration both the intrinsic mechanical properties of graphene and the striking results of our study, we envisage a functional role of this new material as a versatile platform for future biomedical applications in general and stem cell therapies in particular."
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