Focused Session Q-5
Biomedical Applications of Carbon Nanotubes and Graphene: Opportunities and Challenges


Q-5:IL01  Graphene in Biomedical Applications
A. ZURUTUZA, Graphenea S.A., Donostia - San Sebastian, Spain

Graphene and its derivatives have shown a great potential for biomedical applications since their properties (high surface area, tailor-made functionality, etc.) provide excellent biocompatibility, physiological solubility, stability and capability of loading or conjugating different types of compounds. In addition, graphene could also be used in biosensors,1 microelectromechanical systems (MEMS), DNA sequencing,2 etc. During this talk I will cover the potential of graphene to be used in biosensors1 and in targeted treatment of bacteria.3 The biosensors were able to detect the hybridisation of DNA with attomolar sensitivity while the targeted antibacterial treatment was obtained using photothermal therapy. The use of CVD graphene over gold coated surfaces aid the attachment of the DNA to the graphene via π-π or hydrogen bonding interactions. Furthermore, this could be extended to the use of graphene plasmons in sensing applications.4,5 On the other hand, in order to achieve the targeted treatment of bacteria functionalised reduced graphene oxide was used. This therapy could lead to a non-antibiotic based treatment of bacteria.
1. Anal. Chem., 86 (2014) 11211 2. Nano Lett., 14 (2014) 450 3. J. Mater. Chem. B, 3 (2015) 375 4. Nature, 487 (2012) 77 5. Science, 344 (2014) 61

Q-5:IL02  Multifunctional Carbon Nanotubes for Anticancer Therapy
C. MENARD-MOYON, L. MUZI, A. BIANCO, CNRS, Institut de Biologie Moléculaire et Cellulaire, Laboratoire d'Immunopathologie et Chimie Thérapeutique, UPR 3572, Strasbourg, France; I. MARANGON, F. GAZEAU, Laboratoire Matière et Systèmes Complexes, UMR 7057 CNRS-Université Paris-Diderot, Paris, France; G. PASTORIN, Department of Pharmacy, National University of Singapore, Singapore

Carbon nanotubes (CNTs) are promising for applications in nanomedicine, such as diagnosis, disease treatment, imaging, and tissue engineering, owing to their unique properties, large surface area, capacity to cross biological barriers and to be internalised into cells.[1] Surface functionalisation is crucial to increase the biocompatibility of CNTs and impart multiple functionalities. In this talk, I will give some examples of the use of multifunctional CNTs for anticancer therapy. I will explain the strategy we developed to prepare CNTs covalently functionalised with an anticancer drug, a targeting ligand, and a fluorophore.[2] I will also present our work on the assessment of the therapeutic efficiency of two different diameter CNTs loaded with a platinum(IV) prodrug of the anticancer drug cisplatin in their inner core.[3] The smaller diameter CNTs allowed a prolonged release of the encapsulated drug, thus increasing its anticancer efficacy. Finally, I will describe the preparation of CNTs complexed with a photosensitiser to achieve combined photodynamic and photothermal therapy for eradication of cancer cells.[4]
[1] Expert Opin. Drug Discov. 2010;5:691. [2] Chem. Eur. J. 2015;21:14886. [3] Nanoscale 2015;7:5383. [4] Carbon 2016;97:110.

Q-5:IL03  Graphene Water Dispersions! Preparation and Applications
E. VAZQUEZ, Universidad de Castilla-La Mancha, Ciudad Real, Spain

Graphene is considered the ultimate material for applications in many fields, from electronics to composites and biosensors. Biological studies on graphene and graphene oxide are also currently underway in many laboratories for two main aims: (i) the exploitation of the graphene properties in biological applications; (ii) the assessment of the potential toxicity of graphene layers. Graphene is usually prepared by the renowned scotch tape technique or by CVD processes. As such, graphene cannot be dispersed in water or biological media, owing to its complete insolubility. Novel ways to prepare dispersible graphene in water are very much needed. Ball milling of graphite in the presence of melamine has been found in our labs to be a method of choice to exfoliate graphite and generate dispersions of few-layer graphene in many solvents, including water. [1] During this talk, we will discuss (i) optimized ways to generate graphene in solvents using ball milling; (ii) the use of graphene in polymer composites for drug delivery purposes

Q-5:IL04  Light Weight and Flexible High-performance Sensor Platforms for Medical Diagnostics
M. MEYER1, L. BARABAN1, F. PUMP1,2, G. CUNIBERTI1,2,3, 1Institute for Materials Science, TU Dresden, Germany; 2Dresden Center Computational Materials Science, TU Dresden, Germany; 3Center for Advancing Electronics Dresden (cfaed), TU Dresden, Germany

Demographic changes, altering clinical pictures and even unprecedented diseases require innovative approaches for reliable health monitoring platforms. The realization of such devices goes along with great scientific and technological challenges in the convergence area of classical disciplines. In a close collaboration of materials science, electronics and biology, a flexible diagnostic platform has been realized and its performance could be exemplified at the early detection of avian influenza virus (AIV) subtype H1N1 DNA sequences. The key component of the platform is a set of biosensors based on Si-nanowire field effect transistors fabricated on flexible 100 micrometer thick polyimide foils. These devices are about ten times lighter than their rigid counterparts on Si-wafers and can be prepared on large areas. While the latter allows reducing the fabrication costs per device, the former makes them cost efficient for high-volume delivery to medical institutions. Products emerging from our approach offer physicians and patients a reliable and permanent medical monitoring and can be used in medical prevention in many ways. Moreover, our concept offers vast possibilities for further applications not only in the health care sector, but also in industry and in everyday use.

Q-5:IL05  Immunosensor based on Carbon Nanotubes and Graphene
M. HOLZINGER, Département de Chimie Moléculaire, University of Grenoble-Alpes, Grenoble, France

The outstanding properties of nanostructured carbon such as carbon nanotubes or graphene made them a widely used material as electronic or electrochemical transducer in biosensor devices. In particular, carbon nanotubes (CNTs) possess the outstanding combination of nanowire morphology, biocompatibility and electronic properties. Furthermore, their ease and well-documented organic functionalization brings new properties to nanostructured electrodes [1, 2] such as specific docking sites for biomolecules. Moreover, CNT films exhibits a high electroactive surface areas due to the natural formation of highly porous three-dimensional networks, suitable for the anchoring of a high amount of bioreceptor units, leading consequently to high sensitivities. Since several years, monolayer graphene and related 2D carbon materials are shown as promising alternative to CNTs. The presented examples will show some interesting properties of monolayer graphene for SPR biosensors [3] while CNTs remains the material of choice for 3D matrices as receptor-transducer interface for electrochemical biosensor devices.
[1] M. Singh, M. Holzinger, et al. Carbon 2013, 61, 349. [2] M. Singh, M. Holzinger, et al., Carbon 2015, 81, 731. [3] M. Singh, M. Holzinger, et al., JACS 2015, 137, 2800.

Q-5:IL06  Towards NanoMRI with Mechanical Resonators based on Nanotubes and Graphene
A. BACHTOLD, ICFO - The Institute of Photonic Sciences, Castelldefels (Barcelona), Spain

Carbon nanotubes and graphene offer unique scientific and technological opportunities as nanoelectromechanical systems (NEMS). Namely, they allow the fabrication of mechanical resonators that can be operated as exceptional sensors of mass and force. The mass resolution can be as low as 1.7 yg, which is about the mass of 1 proton [1]. The force sensitivity can reach ~1 zN/Hz^1/2 [2,3]. Such a force sensitivity may enable the detection of single nuclear spins by placing the resonator in a strong gradient of magnetic field. Here, I will review our efforts towards the detection of single nuclear spins and the realization of nano magnetic resonance imaging (nanoMRI).
[1] J. Chaste, A. Eichler, J. Moser, G. Ceballos, R. Rurali, A. Bachtold, Nature Nanotechnology 7, 301 (2012). [2] J. Moser, J. Güttinger, A. Eichler, M. J. Esplandiu, D. E. Liu, M. I. Dykman, A. Bachtold, Nature Nanotechnology 8, 493 (2013). [3] J. Moser, A. Eichler, J. Güttinger, M. I. Dykman, A. Bachtold, Nature Nanotechnology 9, 1007 (2014).

Q-5:IL07  Graphene-based Optoelectronic Liquid Sensing Platform
M. STEINER1, M. ENGEL2, R. GIRO1, P.W. BRYANT1, R.F. NEUMANN1, P. AVOURIS2, C. FEGER2, 1IBM Research, Rio de Janeiro, Brazil; 2IBM Research, Yorktown Heights, NY, USA

Graphene, a two-dimensional lattice structure consisting of carbon atoms, possesses unique electronic and optical properties and is currently being investigated as a candidate material for biomedical device applications. Integrated within electronic circuits, graphene allows for the implementation of novel sensing functionalities and analysis methods. Optically transparent graphene-based devices, due to their sensitivity to surface effects such as liquid-solid interactions, can enable the in-situ analysis and the real-time monitoring of tiny amounts of liquids through the simultaneous application of electronic sensing, optical and/or raster scanning microscopy methods. In this talk, we present a graphene-based optoelectronic sensing platform for the application of high-resolution microscopy techniques to nanoscale liquids, such as oil emulsions. Real-time monitoring of liquid dynamics is achieved by simultaneous electronic and optical measurements during liquid deposition. The correlation of optical and electronic data provides unique insight into the surface wetting dynamics on a time scale of tens of milliseconds. Potential applications of the graphene-based platform include chemical and biochemical process analysis for healthcare and life sciences.

Q-5:L09  Graphene and Graphene Oxide Sensors for Monitoring Chronic Wounds
N. CALISI, B. MELAI, P. SALVO, C. PAOLETTI, R. FUOCO, V. MOLLICA, F. DI FRANCESCO, Department of Chemistry and Industrial Chemistry, University of Pisa, Pisa, Italy

The longer life expectancy in Western countries brings forth the new challenge of a growing burden of chronic illnesses. At present, about 1.5 % of people experiences a chronic wound in the course of life. Treatments like compression bandaging for venous leg ulcers or offloading for diabetic foot ulcers lead most wounds to healing, but about 25% remain open without an obvious reason. Wearable sensors are creating great expectations for improving knowledge on the biochemical processes in action in these wounds and combining quality of treatment and low cost. SWAN-iCare is a project funded by the European Commission developing temperature, pH and metalloproteases activity sensors for monitoring and managing chronic wounds, mainly diabetic foot ulcers and venous leg ulcers. We report here the fabrication, testing and validation of disposable sensors, namely a resistive sensor based on reduced graphene oxide for the measurement of temperature and a potentiometric sensor based on graphene oxide for the measurement of pH in the wound bed. In-vitro validation with model solutions and real samples established accuracies of ±0.5 °C (range 20-40 °C) and ±0.2 pH units (range 5.5-9 pH units). Issues concerning biocompatibility for the use in contact with the wound bed are also addressed.

Q-5:IL10  Carbon Nanohorns for Targeted Therapy
EIJIRO MIYAKO, Nanomaterial Research Institute (NMRI), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan

Nanocarbons, such as carbon nanotubes and carbon nanohorns (CNHs), are materials of interest in many fields of science and technology because of their remarkable chemico-physical properties. In particular, nanocarbons possess extraordinary photothermal energy conversion efficiency and high absorption cross sections in a wide wavelength range. In this presentation, this powerful photothermal conversion property of CNHs for targeted therapy will be presented with the examples of several applications.

Q-5:IL11  Carbon-based Substrates for Stem Cell Differentiation
T. NAYAK, C. ZHAO, H. ANDERSEN, H.K. HO, B. OEZYILMAZ, G. PASTORIN, National University of Singapore, Pharmacy Department, Singapore

Recent advances in nanomaterials have led to several opportunities in biomedical research. The current and most promising applications of these nanomaterials include, but are not limited to, drug delivery and tissue repair. In our group we have demonstrated that carbon-based materials might provide a promising biocompatible scaffold in tissue engineering, since they do not hamper the proliferation of human stem cells and accelerate their differentiation into specific lineages. Interestingly, cell differentiation occurred even in the absence of additional biochemical inducing agents, as evidenced by multiple independent criteria at the transcriptional, protein expression and functional levels. Since the differentiation rate is comparable to the one achieved with currently used growth factors, these results pave the way for the potential use of these nanomaterials for stem cell research.

Q-5:IL12  Anodic-electrophoretic Deposited Graphene Oxide onto Anodized Titanium for Orthopaedic Applications
S. SIRIVISOOT, Biological Engineering Program, Faculty of Engineering, King Mongkut’s University of Technology Thonburi, Bangkok, Thailand

Infections in orthopaedic implants are difficult to diagnose and treat early enough to prevent implant failure. In a previous study, we obtained antibacterial and biocompatible titanium (Ti) implants by coating graphene oxide (GO) and osteoinductive hydroxyapatite (HA) onto anodized titanium (ATi). The results of ribonucleic acid leakage tests of Staphylococcus aureus and Escherichia coli revealed that direct contact of the bacteria with GO causes bacterial membrane stress, leading to irreversible damage and bacterial death. Importantly, GO-HA-ATi increased osteoblast proliferation after 5 days and calcium deposition after 21 days in standard cell culture conditions. The increased cell proliferation and differentiation was mainly due to the effects of the HA rather than the GO. The aim of the present study was to study pre-osteoblast responses of anodic-electrophoretic deposition of GO on Ti and ATi alone. The physiochemical properties of the samples were analyzed using energy-dispersive X-ray spectroscopy, X-ray diffractometry, and X-ray photoelectron spectroscopy. Cell proliferation and differentiation of pre-osteoblasts were investigated to predict their ability to enhance juxtaposed bone formation on orthopaedic implants.

Q-5:IL13  Fate of Functionalized Carbon Nanotubes In the Brain: From the in Vitro Interactions to the in Vivo Response
C. BUSSY, Centre for Tissue Injury and Repair, Faculty of Biology, Medicine and Health & National Graphene Institute, University of Manchester, Manchester, UK

Surface tunability and ability to translocate plasma membranes make chemically functionalized carbon nanotubes (f-CNTs) promising intracellular delivery systems for therapeutic or diagnostic purposes in the brain. However the knowledge regarding the interactions of those new delivery systems with the different cells of the brain and how these interactions can affect the overall response of the tissue to be treated is still limited. The first part of the talk will be dedicated to our works at the cellular level. Using different primary neural cells, microglial cells were identified as gatekeeper cells with a key role in response to nanomaterial exposure. Over a 30 day period, microglial cells were also shown to maintain their basic functions, including uptake, adhesion, and mobility, despite a large loading of materials. Finally, the kinetic of degradation of f-CNTs in microglial cells over a period of 90 days was investigated, revealing the key role of surface chemical properties in this process. The second part will focus on some of the in vivo works performed in the lab. Following different stereotactic administrations, the inflammation profile, the in situ degradation and the fate of f-CNTs in the brain will be discussed and compared to other nanosystems.

Q-5:IL15  Risk of Altered Respiratory Immunity Associated with Exposure to Carbonaceous Nanomaterials
A.A. SHVEDOVA, CDC/NIOSH and Dept. Physiology & Pharmacology, WVU, Morgantown, WV, USA; V.E. KAGAN, University of Pittsburgh, Pittsburgh, PA, USA

Unique physico-chemical properties of engineered nanomaterials (EN) make them desirable for a number of novel technological and biomedical applications, including tissue regeneration, drug/gene delivery, and disease monitoring. However, with the expanding of the nano-scale product manufacturing human exposures to EN are rising. Nanotoxicology is an emerging discipline centered on understanding the properties of EN and their interactions with biological systems, and may be viewed as the study of the undesirable interference between man-made nanomaterials and cellular nanostructures or nano-machines. This talk will discuss recognition of engineered nanomaterials by the immune system, our primary defense system against foreign invasion. Additionally, we highlight in vivo studies of the toxicological outcomes of EN, including carbon nanotubes and graphene oxide, with an emphasis on allergic, inflammatory and genotoxic responses. Computational toxicology, the integration of global cellular transcriptomic analysis with advanced computer modeling for high throughput, in silico toxicology testing, aims to evaluate the potential human health effects of the ever growing number of toxicants (EPA, 2014) and is of particular interest in the burgeoning nanotoxicology field.

Cimtec 2016

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