FO - 10th International Conference
Medical Applications of Novel Biomaterials and Nano-biotechnology

Session FO-1 - Advances in Biomaterials

FO-1:IL01  Novel Nano- and Pico-technology Medical Devices: The Future is Here
T.J. WEBSTER, Department of Chemical Engineering, Northeastern University, Boston, MA, USA

Inspired from biological systems, nanotechnology (and more recently, picotechnology) is beginning to revolutionize medicine including the improved prevention, diagnosis, and treatment of numerous diseases. This talk will summarize efforts over the past decade that have synthesized novel nanoparticles, nanotubes, and other nanomaterials to improve medicine. Efforts focused on the use of nanomaterials to minimize immune cell interactions, inhibit infection, and increase tissue growth will be especially emphasized. Tissue systems covered will include the nervous system, orthopedics, bladder, cardiovascular, vascular, and the bladder. Materials to be covered will include ceramics, metals, polymers, and composites thereof. Self-assembled nano-chemistries will also be emphasized.
Thus, this talk will:
. Summarize recent advances in novel materials for medical devices
. Emphasize novel properties of nano and pico-technology derived materials, and
. Identify how such materials can be used to decrease inflammation, infection and improve tissue growth.


FO-1:IL02  Bioinspired 3D Structured Composites
A.R. STUDART, Complex Materials, Department of Materials, ETH Zurich, Switzerland

Natural composite materials like seashells, teeth, bone and trees consist of a soft organic matrix and stiff reinforcing building blocks assembled into unique hierarchical architectures. The intricate organization of such natural materials over multiple length scales finds no counterparts within man-made composites. Implementation of such nano-/microstructural design in synthetic composites should enable the creation of materials with unusual combination of properties and functionalities. Despite ongoing efforts to understand the complex cell-mediated processes that lead to such hierarchical architectures, mimicking synthetically the structural organization of natural materials remains a major challenge. An alternative approach is to devise new directed assembly routes to organize colloidal building blocks into bioinspired structures in the absence of cellular control. In this talk, I will present some of our recent attempts to develop such directed assembly routes. First, I will show a new approach to obtain polymer-based composites exhibiting deliberate orientation of reinforcing particles using ultra-low magnetic fields. The ability to control the position and orientation of reinforcing particles within a polymer matrix leads to bioinspired heterogeneous structures with unusual out-of-plane stiffness, wear resistance and shape-memory effects. In the second part of the talk, I will show that an elastomeric polyurethane matrix can be hierarchically reinforced with nano- and microplatelets to form hybrid materials with local elastic modulus varying up to five orders of magnitude. Control over the local reinforcement level enables the creation of polymeric substrates that can be stretched several times its initial length, while keeping the local strain on specific surface sites lower than 1%. The unusual mechanical properties achieved in these examples illustrate the great potential of nano- and microstructuring in creating synthetic composites with rich functional behavior using a limited set of building blocks.


FO-1:IL03  Macromolecular Crowding: The Next Frontier in Tissue Engineering
D.I. ZEUGOLIS, Network of Excellence for Functional Biomaterials (NFB), National University of Ireland, Galway, Ireland

The driving hypothesis of tissue engineering by self-assembly is that replacement, repair and restoration of lost tissue function can be accomplished best by using cells' inherent capacity to create highly sophisticated structures with efficacy still unmatched by man-made devices. However, the prolonged culture time required to develop an implantable device jeopardises clinical translation and commercialisation. Macromolecular crowding, a biophysical phenomenon that increases thermodynamic activities and biological processes by several orders of magnitude, has only recently been identified as a key in vitro microenvironment modulator. We report that the efficacy of macromolecular crowding in enhancing matrix deposition is amplified in permanently differentiated and stem cell culture in the presence of low serum concentration. In fact, an over 80-fold increase in extracellular matrix deposition is documented within 48h. We identify that macromolecular polydispersity is key modulator of extracellular matrix deposition, due to the generation of effective volume exclusion effect. This approach opens up new avenues in engineering cohesive tissue modules in vitro.


FO-1:IL04  Rapid Prototyping of Biomaterials for Diagnostic, Drug Delivery, and Regenerative Medicine Applications
R.J. NARAYAN, UNC/NCSU Joint Department of Biomedical Engineering, Raleigh, NC, USA

Rapid prototyping (also known as additive manufacturing or 3D printing) is a processing approach that relies on layer-by-layer growth in order to create three-dimensional structures. For example, stereolithography and two photon polymerization are rapid prototyping methods that are used for selective photopolymerization of photosensitive materials. In two photon polymerization, spatial and temporal overlap of photons is used for photopolymerization of material within highly-localized volumes. Several types of polymers, inorganic-organic hybrid materials, and other photosensitive resins have been successfully processed by means of two photon polymerization. Recent developments involving use of novel classes of photosensitive materials and medically-relevant characterization of two photon polymerization-processed structures will be presented. In addition, use of recent developments in rapid prototyping technologies for fabrication of tissue substitutes, biosensors, drug delivery devices, and medical devices will be discussed. For example, use of two photon polymerization for processing of several types of microneedles, which are devices used for transdermal drug delivery, will be considered.


FO-1:IL06  Self-assembled Nanostructured Biomaterials for Biomedical Devices
H. FENNIRI, Northeastern University and Qatar Biomedical Research Institute, Boston, MA, USA

Organic chemistry offers tremendous opportunities for the synthesis of small molecules with the ability to spontaneously self-organize into well-defined supramolecular architectures under a defined set of physical conditions.
Over the past several years we have developed and utilized a new class of heteropolycyclic molecules to explore hydrogen bonding in water, self-replication in auto-catalytic systems, supramolecular chirality, and the underlying physical phenomena of self-assembly and self-organization processes.
With this knowledge in hand, we were able to tailor the chemical, physical, and biological properties of 1-D tubular nanostructures for applications in the emerging fields of organic electronics, photovoltaics, nanobiotechnology, and nanomedicine. This lecture is an overview of the design, synthesis, and physical characterization of self-assembled organic nanotubes, and their biomedical applications.


FO-1:IL07  Self-assembled Green Tea Nanocomplexes for Cancer Therapy
M. KURISAWA, JOO EUN CHUNG, SUSI TAN, SHU JUN GAO, NUNNARPAS YONGVONGSOONTORN, JACKIE Y. YING, Institute of Bioengineering and Nanotechnology, The Nanos, Singapore

(-)-Epigallocatechin-3-O-gallate (EGCG), a major ingredient of green tea, is recognized for its various potential therapeutic effects, including anticancer effects. Herein we introduce the core-shell micellar nanocomplexes (MNCs) spontaneously constructed by the self-assembly of EGCG derivatives and therapeutic protein. This system is the first to utilize EGCG as a carrier for biological molecules aiming at the synergistic therapeutic effects associated with the carrier itself.


FO-1:IL09  Advanced Applications of Bioactive Glasses: Vascularization, Drug Release, Wound Healing and Soft Tissue Regeneration
V.P. MIGUEZ, A.R. BOCCACCINI, Institute of Biomaterials, University of Erlangen-Nuremberg, Erlangen, Germany

The role of bioactive glasses (BGs) as bone substituting materials, bioactive coatings, dental materials and for bone tissue engineering is well known and the key properties of BGs suitable for this purpose, such as a high bioactivity and osteoconduction have been extensively studied. There are however numerous exciting opportunities for the application of BGs in medical areas that go beyond bone and teeth, which can be grouped into: drug delivery systems, wound healing and soft tissue repair and regeneration. Application of BGs in such areas is supported by the investigated effect of BGs on vascularization and angiogenesis. An expanding number of Investigations is being reported on applications of BGs in contact with soft tissues which go beyond a simple assessment of soft tissue-bioactive glass surface attachment and consider the effect of metallic ions released from specific compositions of bioactive glasses, including silicate, phosphate and borate glasses. This presentation will give a broad overview of the latest developments in the field of BGs applied to the enhancement of soft tissue healing and regeneration and will discuss the specific combined effect of chemical composition and morphology of BG-based platforms highlighting suggested avenues for future research.


FO-1:L10  In-vivo Toxicity Evaluation for Nanophosphors as an Alternative to Quantum Dots
GUN HYUK JANG, SU YEON KIM, HO SEONG JANG, KWAN HYI LEE, Korea Institute of Science and Technology (KIST) Seoul, Republic of Korea; University of Science and Technology (UST), Seoul, Republic of Korea

Lanthanide ion-doped nanophosphors are an emerging group of nanomaterials with excellent optical properties, and have been suggested as alternatives to quantum dots. However, the in-vivo toxicity of these emerging nanomaterials has not been systematically evaluated despite the many recent reports in biomedical applications. In this study, we determine the in-vivo toxicity of nanophosphors using early developing zebrafish medels. In particular, we have examined phenotypic developmental abnormalities (growth retardation, heart deformity, and bent tail), apoptotic cell death, and changes in heart function due to the in-vivo toxicity. This study suggests the use of nanophosphors as alternatives for QDs in a wide variety of biomedical applications.


FO-1:L11  Facile in situ Synthesis and Impregnation of Silver Nanoparticles in a Hydrophobic Polymer for Antimicrobial Biomaterials
P.A. TRAN, A.J. O'CONNOR, Department of Chemical and Biomolecular Engineering, Particulate Fluids Processing Centre, The University of Melbourne, Victoria, Australia; D.M. HOCKING, Department of Microbiology and Immunology, The University of Melbourne, Australia

Device-associated infection (DAI) remains a challenge to modern medicine as more patients are being implanted with medical devices that provide surfaces and microenvironments for bacterial colonization. In addition, there is an urgent need for alternatives to antibiotics in preventing and treating these infections as a result of increases in drug resistance. Silver nanoparticles (Ag NPs) have emerged as a promising non-antibiotic antimicrobial agent against a wide range of bacteria. However, for them to be clinically useful, they must be properly incorporated into devices which often possess wetting properties detrimental to not only the incorporation but also the release of such nanoparticles. This study takes advantage of polyethylene glycol to form and stabilize hydrophilic Ag NPs in situ within a hydrophobic polycaprolactone (PCL) matrix. Results showed that Ag NPs were formed in situ and uniformly dispersed in the matrix. Interestingly, lower concentrations of Ag lead to more prolonged release profiles. Importantly, the novel Ag-impregnated PCL had increased antimicrobial efficacy as demonstrated through bacterial testing. This new method has potential to significantly improve the antimicrobial efficacy and ease of fabrication of Ag-containing materials for medical devices.


FO-1:L15  Diopside Glass-ceramics for Dental and Biomedical Applications
J. AL-MUHAMADI, N. KARPUKHINA, M. CATTELL, Centre for Adult Oral Health, Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK

The issue of brittle fracture in most dental restorations has not been overcome yet. This is due to mismatching in thermal expansion coefficient (TEC) between ceramic material and the zirconia substrate (Y-TZP). Recently, diopside (CaMgSi2O6) based ceramics have generated a significant interest in biomedicine and dentistry. The aim of this study is to produce a diopside based glass-ceramics that is thermally compatible with strong Y-TZP ceramics for dental applications.
Glass compositions with increasing Na2O:Al2O3 mol% were synthesised using a melt-quench route, processed into powder and heat treated. Glasses and glass-ceramics were characterised using X-ray diffraction, dilatometry, scanning electron microscopy and solid state nuclear magnetic resonance spectroscopy.
As a result of this study diopside glass-ceramics with unique microstructures and with a thermal expansion coefficient matching strong Y-TZP have been successfully produced. These glass-ceramics may be suitable for crowns and veneering materials. The produced Diopside glass-ceramics could also be a potential candidate for bone replacement/bioactive materials.


FO-1:L16  Systematic Approach to Preparing Ceramic-glass Composites with High Translucency for Dental Restorations
H.N. YOSHIMURA, A. CHIMANSKI, Universidade Federal do ABC, Santo André, SP, Brazil; P.F. Cesar, Universidade de Sao Paulo, Sao Paulo, SP, Brazil

Ceramic composites are promising materials for dental restorations, which can fulfill the needs of high toughness for long lifetime and high translucency for superior aesthetics. However, it is difficult to prepare high translucent composites due to the light scattering that occurs in multiphase ceramics. In this work, a systematic approach was applied to prepare glass infiltrated ceramic composites. First it was necessary to calculate from the literature data the viscosity of glass at the infiltration temperature using the SciGlass® software. Then, the glass compositions were designed for targeted viscosity and refractive index. The glasses of the system SiO2-B2O3-Al2O3-La2O3-TiO2-CaO prepared by melting the oxide raw materials were spontaneously infiltrated into the porous alumina preforms at 1200°C. The optical properties were measured using a refractometer and a spectrophotometer. The light transmittances of the prepared composites were significantly higher than a commercial ceramic-glass composite. The analysis of reflectance measurements by Kubelka-Munk model showed that the superior translucencies of the prepared composites are due to the matching of glass and preform refractive indexes which lowered the scattering, and also to the lowering of the absorption coefficient.


FO-1:L17  Bioactive and Biocompatible Silica/Pseudowollastonite Aerogels
P.J. RESÉNDIZ HERNÁNDEZ, D.A. CORTÉS HERNÁNDEZ, CINVESTAV-IPN, Unidad Saltillo, Ramos Arizpe, Mexico

Silica aerogels have attracted increasingly more attention due to their extraordinary properties and their existing and potential applications in a wide variety of technological areas. Materials that promote bone-tissue formation at their surface and bond to osseous tissues when implanted are called bioactive, such as pseudowollastonite particles.
In this work, the synthesis of aerogels with pseudowollastonite particles was performed. The synthesis involved the preparation of an alcogel by a two step sol-gel route followed by ambient pressure drying. To promote a higher bioactivity the obtained aerogels were then biomimetically treated using simulated body fluids, SBF and 1.5 SBF. A high bioactivity was demonstrated by FT-IR, SEM, EDS, TEM and XRD. The in vitro biocompatibility was assessed by testing cytotoxicity using rat osteoblasts. The results obtained indicate that these materials are highly potential aerogels for bone tissue regeneration.


FO-1:L18  Biocompatible Hydroxyapatite Nanotubes
B.B. CHANDANSHIVE, D. KHUSHALANI, Materials Chemistry Group, Department of Chemical Sciences, Tata Institute of Fundamental Research, Colaba, Mumbai, India 

Functional biomaterials can be used as drug loading devices, components for tissue engineering or as biological probes. Presented here is the synthesis of stoichiometrically pure, porous hollow hydroxyapatite nanotubes and single-particle analysis has been extensively performed to successfully prove the sole formation of HAp phase. The facile synthesis involves a sol-gel process under neutral conditions in the presence of a sacrifical anodic alumina template. The structures formed have been characterized by XRD, SEM, TEM, SAED, EELS, EDS and BET measurements. The diameter of the resulting tubes is in the range of 140-350 nm, length is on the order of a few microns and the wall thickness of the tubes is ca. 30 nm. The synthesis has been extended to form luminescent HAp nanotubes by encorporating Tb3+ ions into the structure which allowed facile direct imaging of the tubes and the tubes were tested for biocompatibility using MTT assay. Furthermore, direct imaging in the presence of fibroblast cells was performed using FRET pair SYFP-TQ. Compositional and structural changes were extensively studied using photo PL measurements and confocal microscopy to study the capability of the HAp nanotubes to be readily endocytosed in the cell without deleterious effects.


Session FO-2 - Enabling Tools

FO-2:IL01  Cell Manipulation and Processing using Inkjet Printing
B. DERBY, R. DOU, R.E. SAUNDERS, School of Materials, University of Manchester, UK; C. WARD, School of Dentistry, University of Manchester, UK

Inkjet printing is a highly versatile method for the precise positioning and patterning of cells. It is a non-contact method for patterning surfaces with very small droplets of ink (typically picolitres). In addition, because it is a liquid dispensing method, it is possible to dispense biological materials in an aqueous environment at physiological temperature. It is now well established that a range of cell types, including human embryonic stem cells, can be printed successfully using this method.
It is possible to print discrete patterns of cells that maintain their position on a substrate. We also show that it is possible to produce patterned cell sheets that can be removed after reaching confluence on suitable surfaces showing temperature controlled cell adhesion. This allows the construction of more complex tissue analogue structures through sheet stacking.
Finally we show that it is possible to combine inkjet printing with cryopreservation methods, to preserve nanolitre volumes of cell suspensions with high cell survivability after freeze-store-thaw cycles.


FO-2:IL02  Miniaturized CMOS Imaging Devices to Measure Brain Neural Activities of Freely-moving Mice
J. OHTA, Graduate School of Materials Science, Nara Institute of Science and Technology, Ikoma, Japan

For studying memory and learning, it is important to measure brain neural activities of freely-moving mice, because behavior experiments are essential in the studies. We have been developing a micro CMOS imaging device that can be implanted in the deep brain of a mouse. The device can measure neural activities with the spatial resolution of a few tens microns in real-time. The device structure and fundamental performance for in vivo experiments are demonstrated in the presentation.


FO-2:L03  Understanding Interactions of Nanomaterials with Biological Environment: Insights from Simulations
I. YAROVSKY, Health Innovations Research Institute, RMIT University, Melbourne, Australia 

The sophisticated tailoring of surfaces to control the interactions between synthetic materials and biomolecular systems is one of the key aims of nanomedicine today. Recent studies suggest that proteins bind differently to nano-patterned materials and this concept holds a great potential for engineering of novel materials for biomedical applications. At the same time, there is already sufficient evidence that engineered nanomaterials can cross the BB barrier as well as enter other organs where they can interfere with the biological molecular machinery. Theoretical modelling can help get insights into the molecular mechanisms of biomolecule interactions with nanomaterials which can be exploited to improve molecular recognition needed in biosensors, tissue engineering and drug delivery applications. It can also help understand some unintended undesirable consequences of the presence of nanomaterials in biological environments. In this talk several examples based on our recent [1-2] and current work will be presented.
1. A. Hung, S. Mwenifumbo, M. Mager, J. Kuna, M. Hembury, F. Stellacci, I. Yarovsky, M.M. Stevens, JACS, 133 (2011) 1438.
2. A. Hung, M. Mager, M. Hembury, F. Stellacci, M. M. Stevens, I. Yarovsky, Chem. Sci., 4 (2013) 928 [front cover]


FO-2:L05  Separation of Cells in Multiphase Systems
O. AKBULUT, Z.P. GUVEN, G. AVCI, M. COKOL, Sabanci University, Istanbul, Turkey

Obtaining homogeneous populations from heterogeneous mixtures is a prevalent problem in many fields and easy-to-use and cost-effective toolboxes can facilitate new types of separations. Whitesides group at Harvard University has recently shown that several water-soluble polymers can form multiphase systems which can be utilized as centrifugation media in density-based and dynamic separations of organic and inorganic materials. [1,2] These systems have a common solvent, water, and the interfaces constitute thermodynamically stable barriers to capture the targets of interest (i.e., cells). They possess several advantages compared to the current density-based separation media such as sucrose gradients. Here, we will present the separation of different types of cells such as bacteria, yeast and mammalian cells in these systems.
1) Mace, C.R.; Akbulut, O.; Kumar, A.A.; Shapiro, N.D.; Derda, R.; Patton, M.R.; Whitesides, G.M. Aqueous multiphase systems of polymers and surfactants provide self-assembling gradients in density. J. Am. Chem. Soc. 2012, 134, 9094-9097.
2) Akbulut, O.; Mace, C.R.; Martinez, R.V.; Kumar, A.A.; Nie, Z.; Patton, M.R.; Whitesides, G.M. Separation of nanoparticles in aqueous multiphase systems through centrifugation. Nano Lett. 2012, 12, 4060-4064.


FO-2:IL06  Surface Modulation of Carbohydrate Ligands on Cells Using Polymerization Technique
Y. IWASAKI, M. SAKIYAMA, S. FUJII, Department of Chemistry and Materials Engineering, Kansai University, Suita, Osaka, Japan

The cell surface can be considered as among the most sophisticated materials generated in nature. The cell surface engineering with synthetic molecules will provide robust materials having bioactivities governed by cell surface molecules. In the current study, synthetic polymers were immobilized on mammalian cell surfaces and then the biointerfacial aspects of the immobilized polymers were characterized.
N-methacryloyl mannosamine (ManMA) was synthesized as an artificial precursor of sialic acid. The ManMA was in contact with human promyelocytic leukemia cells (HL-60) and incubated. Confirmation of delivery of the methacryloyl groups to the cell surface was performed by a thiol-ene reaction. When thiol-terminated 4-arm poly(ethylene glycol) was immobilized ManMA-treated cells, anti-PSGL-1 reactive band with the higer molecular weight was observed by western blotting analysis data.
Thermoresponsive poly(N-isopropylacrylamide) was also immobilized on HL-60 surface and separation of PNIPAM-conjugated glycoproteins was successfully performed.
Because the process for the surface modification of mammalian cells is tolerated in various types of cells, a great variety of biological applications will be performed.


FO-2:IL08  Smart Biomaterials for DNA Analyzing Tools
M. MAEDA, Bioengineering Laboratory, RIKEN Institute, Wako, Saitama, Japan

MicroRNAs (miRNAs) are short and non-protein-coding single-stranded RNAs and one of the promising biomarkers for cancers. Some miRNAs circulate in human body fluid with extremely low concentrations at the early stage of cancer, and its expression profiling can detect or classify cancer in the human body. In this study, rapid and sensitive miRNA detection utilizing power-free microfluidic chip, which is driven by degassed poly (dimethylsiloxane), thus eliminating the need for an external power supply, is demonstrated. We have found that the double-stranded DNA-carrying Au nanoparticles acquires high colloidal stability to disperse in an aqueous medium when a terminal single-base mismatch exists at the interface between the DNA corona and the disperse medium. Exploiting the unique colloidal behavior of the DNA-functionalized Au nanoparticles, we have developed a microfluidic device for the detection of the microRNAs. In addition, we have improved the detection system for higher sensitivity. When microRNAs are detected through sandwich hybridization and the signals are amplified by laminar flow-assisted dendritic amplification, we have detected microRNAs of specific sequences at a limit of detection of 1 pM from a 0.5 μL sample solution with a detection time of 20 min.

 
Session FO-3 - Medical Diagnostics and Imaging

FO-3:IL01  Infrared Sensors Inspired by Pyrophilous Insects
H. BOUSACK, Forschungszentrum Jülich, Jülich, Germany; H. SCHMITZ, Universität Bonn, Bonn, Germany; M. SCHOSSIG, Technische Universität Dresden, Dresden, Germany

Nature offers amazing solutions that inspire us to design new technical applications. In the animal kingdom we find a lot of biological sensors with outstanding skills. One example is the beetle Melanophila acuminata, which is highly dependent on forest fires. The adults put their eggs in the freshly burned trees and the burned wood serves as food for the larvae. To be able to detect forest fires from far distances the beetle developed a highly sensitive infrared receptor which works according to a photo-mechanical principle. The beetle has two pit organs, one on each lateral side, of which each houses around 70 domeshaped infrared receptors.
The structure and the function the receptors will be introduced as a basis for a thermodynamic model that explains the influence of the main design factors such as geometry, fluid and infrared power density. Until now it was not possible to determine consistent data regarding the infrared sensitivity of the beetles. With a new approach the sensitivity could be estimated about 2 orders of magnitude below thermal noise which requires special methods of the beetles to detect the fire signals buried in the noise.
First attempts have been undertaken to build sensors using the photo-mechanical principle. Here the critical issues are the choice of the fluid and the read-out of the tiny membrane deflection.


FO-3:IL02  Novel Nanostructured Sensors for Orthopaedics
S. SIRIVISOOT, Biological Engineering, Faculty of Engineering, King Mongkut's University of Technology Thonburi, Bangkok, Thailand 

Bacterial infection is a major cause of orthopaedic implant failure. If not treated, infection can rapidly spread, leading to inflammation, or eventually revision surgery. In the present study, we investigated the use of graphene oxide-apatite electrodeposited on anodized titanium as an in situ method of monitoring bacterial contamination on titanium, which is widely-used for orthopaedic implants. Our findings suggested that this nanostructured platform could immediately alert us to the build-up of specific bacteria on the titanium by generating a unique electrical current. Staphylococcus aureus and Escherichia coli, commonly associated with bone implant infection, were used in this study as Gram-positive and Gram-negative models, respectively. Moreover, the antibacterial properties of graphene oxide were investigated by an antibacterial droptest and assessment of the efflux of the bacterial RNA. A cytocompatibility test with human pre-osteoblasts, bone-forming cells, was also performed to explore the potential use of graphene oxide-apatite electrodeposited on anodized titanium as an in situ sensor to detect early bacterial infection in orthopaedics.


FO-3:L06  Analytical and Theranostic Applications of Plasmonic Nanoparticles and Nanocomposites
N.G. KHLEBTSOV, V.A. BOGATYREV, L.A. DYKMAN, B.N. KHLEBTSOV, E.V. PANFILOVA, T.E. PYLAEV, V.A. KHANADEEV, Institute of Biochemistry and Physiology of Plants and Microorganisms, Russian Academy of Sciences and Saratov State University, Saratov, Russia; G.S. TERENTYK, V.V. TUCHIN, Saratov State University, Saratov, Russia

In the past decade gold nanoparticles (GNPs) have been widely used in various biomedical applications [1]. Multifunctional nanocomposites that combine therapeutic, diagnostic, and sensing modalities in a single nanostructure are widely used in a new field of nanobiotechnology called theranostics. Although the term "theranostics" has been introduced quite recently, it is now rapidly growing and promising field at the crossroads of plasmonics and nanomedicine. In this talk we summarize our recent efforts in analytical and theranostic applications of engineered GNPs and nanocomposites by using plasmonic properties of GNPs and various optical techniques [2]. Specifically, we provide examples of SERS platforms for analytical biosensing; dot immunoassay and GNP-enhanced PCR diagnostics; visualization and bioimaging of cells; combined photodynamic and photothermal treatment of pathogenic bacteria and xenografted tumors; materno-embryonic transfer of GNPs in pregnant rats.
1. Dykman L.A., Khlebtsov N.G. Gold Nanoparticles in Biomedical Applications: Recent Advances and Perspectives. Chem. Soc. Rev., 41, 256-83, 2012.
2. Khlebtsov N. et al. Analytical and theranostic applications of gold nanoparticles and multifunctional nanocomposites. Theranostics, 3, 167-80, 2013.

 
Session FO-4 - Tissue Engineering and Regenerative Medicine

FO-4:IL02  Next Generation Materials for Hard and Soft Tissue Repair
S. BEST, Department of Materials Science and Metallurgy, University of Cambridge, Cambridge, UK

Advances in regenerative medicine depend on the development of materials which are bioactive, and which are able to control the biological processes in adjacent tissues. This talk will describe the innovation of several types of materials for a range of skeletal and soft tissue repair applications. Hydroxyapatite is a calcium phosphate that is chemically similar to bone mineral. Over a number of years we have studied the effects of additional ions in the lattice structure including carbonate, zinc and also silicon on biological response of the incorporation of carbonate and silicate ions in the hydroxyapatite crystal lattice for bone grafting applications. However calcium phosphates can also be used as a bioactive reinforcing phase in synthetic polymer matrices to produce bioactive, biodegradable composites. We have studied the effects of the addition of different members of the calcium phosphate family into poly(hydroxy acids) for control of degradation and drug delivery. We have also explored the use of freeze drying to produce natural polymer-based systems for treatments ranging from reconstruction of cartilage defects to cardiac applications and we are able to functionalise the surfaces of these materials to optimise tissue repair.


FO-4:IL03  Regenerative Engineering: The Regeneration of Complex Human Tissues
C.T. LAURENCIN, R. JAMES, University of Connecticut Health Center, Institute for Regenerative Engineering, Farmington, CT, USA

Musculoskeletal injuries in the United States cost more than $30 billion annually and are largely constituted of trauma and degenerative pathology. The increasing demand for biologically compatible donor tissue and organ transplants far outstrips the availability leading to an acute shortage. 'Regenerative engineering', defined as the combination of classical top-down tissue engineering approaches with bottom-up strategies used in regenerative biology, represents a new multidisciplinary paradigm to engineer or reconstruct complex tissues. We seek to incorporate our understanding of tissue development to design tissue-inducing biomaterials, structures and composites than can stimulate the regeneration of complex tissues, organs, and organ systems through location-specific topographies and physico-chemical cues incorporated into a continuous phase. Starting with simple structures, we have developed composite and multi-scale systems that closely mimic the native tissues such as such as bone, ligament, tendon and muscle. Ultimately, we aim to modulate the regenerative potential, including proliferation, phenotype maturation, matrix production, and apoptosis through cell-scaffold and host-scaffold interactions developing complex tissues and organ systems.


FO-4:L05  Bioglass Scaffolds Reinforced by Microfibrillated Cellulose Coating 
L. BERTOLLA, I. DLOUHÝ, Institute of Physics of Materials ASCR, Brno, Czech Republic; A. PHILIPPART, A.R. BOCCACCINI, Institute of Biomaterials, Department of Materials Science and Engineering, University of Erlangen-Nuremberg, Erlangen, Germany

The present work deals with the preparation and characterization of Bioglass® porous scaffolds reinforced by microfibrillated cellulose (MFC). Samples were produced by foam replication process and a structure with nominally 90% of open porosity and ~ 200 µm mean pore size was achieved. The coating was obtained by dipping the samples into an aqueous solution of MFC. Tensile tests were conducted on produced samples according to a new testing methodology optimized for highly porous ceramics. The addition of the coating led to a 10 fold increase of tensile strength. SEM observations on broken struts surfaces proved the reinforcing and toughening effect of the coating due to crack bridging and fracture of cellulose fibrils. Therefore, the fracture of MFC fibers contributed to the energy dissipation process which led to the increase of the toughness of the scaffolds.


FO-4:L07  Development of Biomimetic 45S5 Bioglass® and Boron-containing Bioactive Glass Scaffolds by Surface Functionalization with Alkaline Phosphatase for Bone Tissue Engineering Applications 
P. BALASUBRAMANIAN¹, L. HUPA², A.R. BOCCACCINI¹, ¹Department of Materials Science and Engineering, Institute of Biomaterials, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany; ²Abo Akademi University, Finland

Biomimetic strategies are crucial for developing optimized scaffolds for bone regeneration. In this study, we used 3 types of silicate-based bioactive glasses: 45S5 Bioglass® (composition in wt%: 45 SiO2, 24.5 Na2O, 24.5 CaO, 6 P2O5), 1806 bioactive glass (65 SiO2, 15 CaO, 18.4 Na2O, 0.1 MgO, 1.5 B2O3) & 0106 bioactive glass (50 SiO2, 22.6 CaO, 5.9 Na2O, 4 P2O5, 12K2O, 5.3 MgO, 0.2 B2O3). We fabricated robust, highly porous 3D bioactive glass scaffolds by the foam replica technique. Functionalizing the surfaces of these bioactive glass scaffolds with biologically active molecules is a suitable strategy to enhance both the inorganic & biological responses of the biomaterial and to stimulate physiological tissue regeneration. Alkaline Phosphatase(ALP) is a metalloenzyme involved significantly in osteogenesis and is highly expressed in mineralized tissue cells. Silanization and ALP grafting was done on the surface of the 45S5 Bioglass®, 1806 and 0106 bioactive glass scaffolds. Silanization & ALP grafting was confirmed by XPS analysis & enzymatic activity test. 45S5 Bioglass®, 1806 & 0106 bioactive glass scaffolds possess different levels of bioactivity and therefore, we investigated for the first time the influence of ALP in hydroxyapatite formation after invitro bioactivity studies.


FO-4:L08  Novel Microfabrication of 3D Composite Lattice Scaffold for Bone Tissue Engineering 
D. NADEEM¹, M. DALBY², GANG LI³, BO SU¹, ¹Biomaterials Engineering Group, School of Oral & Dental Sciences, University of Bristol, UK; ²Centre for Cell Engineering, University of Glasgow, UK; ³School of Biomedical Sciences, Chinese University of Hong Kong, China

Scaffold is one of the key elements in tissue engineering. Albeit many fabrication techniques have been developed, an 'ideal' scaffold which supports both biological activities and mechanical functionalities is still yet to be realised. The work presented details the microfabrication of a novel micropatterned composite scaffold comprised of HA, TCP and gelatin. Using a top-down approach layers of a micropatterned green ceramic composite tape were micromachined through CNC machining. Multiple lattice layers were then laminated together to construct a 3D scaffold. Porosity of the scaffold was controlled through alteration of the lattice geometry. Evaluation of machining quality showed an excellent finish with well defined edges. Optimisation of tape plasticity was found to further improve machining quality and also enabled higher lattice porosities to be attained by aiding minimisation of the lattice geometries. The lamination of the lattice layers were also incorporated with electrospun nanofibres and surface micropatterning. The mesh of nanofibres acts as a net during cell seeding to optimise cellular infiltration and attachment to the scaffold. The embossed microtopographies further support cellular adhesion, proliferation and differentiation. The novel microfabrication provides a promising new platform for the fabrication of multifunctional bone tissue engineering scaffold.

 
Session FO-5 - Targeted Delivery, Controlled Release Systems and Nanotheranostics

FO-5:IL01  Reconstituted Stem Cell Nano-ghost: Nature Inspired Targeting Platform
M. MACHLUF, Faculty of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa, Israel

The ultimate goal in cancer drug- and gene delivery is a ‘magic-bullet’ that provides a versatile platform for site-specific targeting of multiple cancers, implemented in a clinically relevant and non-toxic design. We have designed a novel delivery platform, which is based on unique cell-derived nano-ghosts (NGs) produced from whole cell membranes of mesenchymal stem cells (MSCs). MSC are well known for their natural targeting of multiple cancers and hypo-immunogenicity. Encompassing MSC surface proteins and armed with their unique targeting capabilities, the MSC-NGs may be loaded with various drugs and nucleic acids and can be selectively targeted against multiple cancers. Such a universal targeting platform can meet the three major prerequisites for an ideal delivery system: biocompatibility, long circulation time, and selectivity. It also represents a much more clinically relevant approach than conventional delivery systems as it avoids the elaborate production and incorporation of targeting moieties into drug-delivery vehicles.
Demonstrating its efficacy on prostate tumors, we will elaborate on its specificity and the wide range of applications, which such platform can clinically address. The NGs platform can contribute to our understanding of cancer progression and can readily be extended to cancer imaging and diagnostics, paving the way to possible treatments of other diseases, manifested by the expression of unique targetable ligands.


FO-5:IL02  Programmable, Targeted Drug Delivery for Musculoskeletal Regenerative Engineering
TAO JIANG, W.H. LO, C.T. LAURENCIN, Institute for Regenerative Engineering, University of Connecticut Health Center, Farmington, CT, USA 

Musculoskeletal diseases such as osteoporosis and osteoarthritis affect the quality of lives of millions of people worldwide. Current clinical treatment methods such as daily injections of human parathyroid hormone for osteoporosis and multiple injections of hyaluronic acid for knee osteoarthritis face significant patient compliance obstacles. In addition, drug delivery that is not site specific may incur adverse side effects. We have developed microscale and nanoscale drug delivery systems fabricated from biodegradable polymer poly(lactide-co-glycolide) (PLGA). Specifically, PLGA particles with sizes ranging from 200 nanometers to several hundred micrometers are synthesized. A combination of PLGA particles with varied lacitde to glycolide ratios and/or sizes leads to the development of programmable drug delivery devices, releasing encapsulated drugs in a pulsatile characteristic during a prolonged time period. In addition, we have developed strategies to modify the PLGA particle surface with functional small peptide sequences. Such surface modified particles are able to target diseased tissues such as osteoporotic bone or osteoarthritic cartilage. It is believed that these PLGA drug delivery devices may find important applications in musculoskeletal regenerative engineering.


FO-5:L03  Development of Novel Mesoporous Silica-based Bioactive Glass Scaffolds with Drug Delivery Capabilities
A. PHILIPPART, A.R. BOCCACCINI, Institute of Biomaterials, University of Erlangen-Nuremberg, Erlangen, Germany

Bioactive glasses are widely used in bone tissue engineering (BTE) since they can develop strong bonds with bone through the formation of a hydroxyapatite (HA) layer. Within these materials, mesoporous bioactive glasses (MBGs) are attractive due to their large surface area and their capacity of being functionalised with a large variety of moieties.
The aim of this project was to develop new MBGs for 3D porous scaffolds fabrication with drug delivery capabilities. The selected glass composition, synthesised by sol-gel method and replication technique, was (in mol) 60%SiO2-30%CaO-5%Na2O-5%P2O5. The scaffold's surface was then functionalised by post-condensation of amino groups and loaded with a model drug.
These MBGs were successfully prepared, and the fabricated scaffolds proved to develop a thick HA layer in Simulated Body Fluid after 12 hours, as revealed by Fourier Transform Infrared Spectroscopy. The mesoporous structure was evaluated by Transmission Electron Microscopy and N2 adsorption porosimetry using the Brunauer-Emmett-Teller approach. In addition, the obtained scaffolds presented the required macropore size (~500μm) and interconnectivity for BTE, according to Scanning Electron Microscopy studies. The load and release of the drug was investigated by UV-Vis spectrometry.


FO-5:L05  New Family of Bioactive Glass Based Scaffolds with Drug Delivery Capability for Bone Regeneration
E. BOCCARDI, A. PHILIPPARD, A.R. BOCCACCINI, Institute of Biomaterials (WW7), Erlangen, Bayern, Germany

The design, fabrication and characterization of a new family of multifunctional scaffolds based on bioactive glass for bone tissue engineering and regenerative medicine applications will be presented. These based scaffolds are developed via replication of synthetic polymer foams (polyurethane) and natural marine sponges. A comparative characterization of these 3-D substrates will be presented, focusing on pore morphology (SEM), pore size distribution (μ-CT) and mechanical properties (compression strength test). Using natural marine sponges as sacrifical template leads to an increase of the mechanical behavior and the possibility to obtain hierarchical pore structure involving not only pores with a diameter in the range 150-500μm, necessary to induce bone ingrowth, but also pores within the 0-200μm range which are required for complete integration with surrounding tissue and neovascularization. To increase the functionality for tissue engineering therapeutics, scaffolds are coated with mesoporous silica particles (MCM-41) which should act as an in-situ drug delivery system. In this way it is possible to obtain a multifunctional system, combining the bioactivity of the macroporous bioactive glass foams with the drug up-take and release properties of MCM-41 silica sub-micron spheres.


FO-5:L07  Engineered Nanotubular Structures for Multifunctional Medical Implants
T. SHOKUHFAR, Department of Mechanical Engineering, Michigan Technological University, Houghton, Michigan, USA; Department of Restorative Dentistry, College of Dentistry, University of Illinois at Chicago, Chicago, IL, USA

Engineered-nanotubular structures offer exciting progress toward the design of multifunctional medical implants. To bring this to reality, the mechanical, physical, biocompatibility, and interfacial properties of such structures should be optimized. We have observed that the fabrication of TiO2 nanotubes with elastic modulus close to actual bone promotes osteoblast growth. In addition TiO2 nanotubes could be considered a suitable alternative route for the development of drug-eluting antimicrobial implants due to the fact that these nanostructures are not an added coating but rather are rooted in the implants and will not delaminate from the surface. Such drug-eluting implants can prevent unnecessary side effects caused by oral administration of drugs, increase drug efficiency, and prevent infection related implant complications and failures.
In the present work TiO2 nanotubes with controllable size (Ø60-130nm, L: 1-10μm) synthesized by a simple electrochemical anodization technique are used as drug-eluting nanostructures on the surface of rat mini implants. This ability to control the aspect ratio of TiO2 nanotubes, gives an opportunity to manage their drug-eluting properties for optimal implant function. Sodium naproxene (anti-inflammatory drug) are loaded into TiO2 nanotubes by using the mass-scalable method of self-sustained diffusion at room temperature and pressure.
In order to obtain a multifunctional implant, in addition to drug, silver nanopartilces were embedded within the nanotubes Transmission Electron microscope (TEM) analysis reveals the presence of Ag embedded inside and outside of the TiO2 nanotubes. Energy-dispersive X-ray spectroscopy (EDS) analysis confirmed the presence of Ag on the TiO2 nanotubes. This multifunctional surface is expected to perform superiorly mainly because Ag is embedded into the nanotubes resulting in more stable bonding between Ag and nanotubes, creating a slow, constant and controlled release of Ag ions to kill bacteria, and simultaneously create a minimum hazardous environment to the cells. 
Finally, in order to investigate the effect of nanotubes on behavior of osteoblast cells, a novel cell/surface interfacial characteristic approach using focused ion beam milling (FIB) and scanning transmission electron microscopy (SEM) techniques was developed. With this novel approach it was possible to cut through sections of cells and the underlying substrate and directly observe the biophysical interactions of osteoblasts with TiO2 nanotubes.  The results of this approach show a tight interface where TiO2 nanotubes act as anchoring sites for osteoblasts to attach and even grow inside the hollow section of nanotubes. This tight interaction would eventually result in enhance bon-implant interlock.
Based on these findings, it is possible to speculated that surface modification of Ti implants by a silver embedded drug-eluting TiO2 nanotubes can provide a novel engineered nanostructure implant for ideal tissue regeneration and antimicrobial benefits at the tissue - implant interface.


FO-5:IL08  Comparison of Intestinal Permeation Enhancers for Delivery of Poorly Absorbed Oral Drugs
D.J. BRAYDEN, J. GLEESON, S. SLADEK, F. McCARTNEY, School of Veterinary Medicine and UCD Conway Institute, University College Dublin, Ireland 

Oral absorption of peptides, proteins and macromolecules is one of the great challenges in the drug delivery field. While these molecules have drawbacks of sensitivity to stomach acid and pancreatic peptidases, such issues can largely be overcome by formulation in coated tablets with peptidase inhibitors and organic acids, which release payload in the small intestine. The bigger hurdle is inability to drive molecules across the intestinal epithelium to generate sufficient oral bioavailability. This will require selection of optimal permeation enhancers in formulated constructs. We have used in vitro and in vivo screening tools to assess the efficacy and toxicity of a range of common and novel excipients and biomaterials in enabling such delivery. Methods comprise Caco-2 monolayers, high content analysis, intestinal tissue mucosae mounted in Ussing chambers, as well as rat in situ intestinal instillations. Results show that medium chain fatty acid type agents,co-polymer surfactants, and alkyl maltoside-based structures can be rank-ordered in terms of efficacy as enhancers in different intestinal regions, taking into account their different cytotoxicity profiles and mechanisms of actions. These data allow for enhancer selection for solid dose and nanoparticle formulation.


FO-5:IL09  Designing Lipid-substituted Cationic Polymers for Gene Based Medicines
H. ULUDAG, H.M. ALIABADI, L. ROSE, B. LANDRY, J. VALENCIA, REMANT K.C., Departments of Chemical & Materials, and Biomedical Engineering, University of Alberta, Canada

We have been designing lipid-incorporating cationic polymers for delivery of nucleic acids (siRNA and plasmid DNA), effectively assembling the macromolecules into nano-sized particles suitable for cellular uptake. Lipids in cationic polymers reduced the binding capability to nucleic acids, which needs to be compensated during nanoparticle assembly. An inverse correlation between the ability of nanoparticles to dissociate and delivery into cells was noted, indicating the need for stable assembly for membrane crossing. We found the same amphiphilic materials to be functional for delivery of both siRNA and plasmid DNA into human cells. It was possible to express therapeutic proteins (e.g., BMPs) in primary bone marrow stromal cells, suitable for regenerative medicine. The level of gene expression was similar to levels of expressions obtained with some viral systems reported in the literature. Silencing aberrant genes in cancer cell lines was also possible with lipid-substituted polymers and siRNA delivery, with desirable therapeutic responses. Our studies indicate a close relationship between the molecular details of lipid-substitution and physicochemical properties of nanoparticles. The engineered biomaterials will be useful delivery systems for clinical studies.


FO-5:IL10  Designing Cytocleavable Polyrotaxanes as a Vehicle for Molecular Logistics of Biomacromolecular Delivery into Target Cells
N. YUI, A. TAMURA, J.-H. SEO, N. YOKOYAMA, G. IKEDA, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan 

Improving intracellular uptake of macromolecules and their bioavailability has been of great interest in order to develop efficient and safe therapeutic drug delivery systems and intracellular diagnostic systems. In the course of our systematic studies on supramolecular biomaterials, it has been clarified that the supramolecular architecture and cytoplasmic dissociation of cytocleavable polyrotaxanes are efficient in inducing the intracellular uptake and exhibiting the therapeutic effects, respectively, compared with any other conventional macromolecules for intracellular delivery systems. In this paper, the effect of polyrotaxane frame on the intracellular uptake, the endosomal escape to cytoplasm, and the cytoplasmic delivery of biomacromolecules such as siRNAs and enzymes is studied by a series of polyrotaxanes composed of tertiary aminated alpha-cyclodextrin (CD) molecules threaded onto a poly(ethylene glycol) chain capped both terminals with bulky amino-acid via disulfide or ester linkages. From the results, it is strongly suggested that the number of threading CD molecules affecting polyrotaxane rigidity and CD mobility along the PEG chain is one of the important valuables to dominate the efficiency of these intracellular events.

 
Session FO-6 - Materials for Neural Interfaces and Implantable Neural Devices

FO-6:IL01  Neuron-electronic Hybrid Systems for Cultured Neurons: From Extracellular to In-cell Recordings by Electrode Engulfment or Cell Electroporation
M.E. SPIRA, The A. Silberman Life Sciences Inst. & H. Kruger Nanoscience center, The Hebrew University of Jerusalem, Israel

Long-term, multisite recording and stimulation of neurons by microelectrode arrays has been the subject of intense studies for decades. Nonetheless, to date these efforts have failed to provide satisfactory technologies that enable the interfacing of individual neurons with electronic device for long-term recording of the entire neuronal repertoire of synaptic- and action-potentials.
In this presentation I describe how we better integrate manmade electronics with individual neurons. To that end we fabricated protruding microelectrodes that mimic the dimensions of dendritic spines. The gMµE are then chemically functionalized to “lures” the cells to actively engulf the electrodes. The gMµE engulfment is executed while maintaining the cell’s plasma membrane intact. The formed neuron/gMµE configuration provides unprecedented long-term, noninvasive recording and stimulation of action potential and subthreshold synaptic potentials from individual neurons with qualities equivalent to intracellular microelectrodes that operate by breaking the neuron plasma membrane. The junction formed between neurons and none functionalized gMµEs revealed only extracellular biphasic action potentials. Electroporation of the plasma membrane transforms the extracellular neuron/gMμE configuration to intracellular. Autonomous repair mechanisms seal the electropores within ~10 minutes. The prospective of the two approaches will be discussed.
Supported by: EU FP7 Grants # 280778 & 306502


FO-6:IL02  Nanowires: A Promising Tool for Neural Implant Applications
C.N. PRINZ, Division of Solid State Physics, Nanometer Structure Consortium and Neuronano Research Center, Lund University, Lund, Sweden 

Nanowires are widely used in biology, for instance as cell transfection devices and cellular sensors. Nanowires have also been shown to record neuronal signals in vitro with minimal cell perturbation and are thus expected to play a major role in the development of neural implants. Our work deals with the investigation of the interactions of nanowires with living cells and tissues. We have shown that neurons from both the peripheral and central nervous system thrive on gallium phosphide nanowires. In the case of retinal cells, nanowires elicit extensive neurite outgrowth without favoring spreading and adhesion of glial cells. By making alternating patterns of nanowire arrays and flat substrate, we were able to confine the glial cells on the flat areas while most neurons grow on the nanowires. The distinct behavior of neurons and glial cells on nanowires may be explained by difference in cell proliferation rates and motility. We have also investigated the in-vivo biocompatibility of nanowires in the brain. A nanowire suspension was implanted into the adult rat striatum. We showed that the inflammatory microglial cells ”collected” most of the nanowires. Our data also suggested that some nanowires have been degraded and/or transported away from the injection site. No signs of sub-acute or chronic nanowire toxicity was detected.


FO-6:IL03  New Generation CNT-based Biochips for Interfacing the Central Nervous System
L. BALLERINI, University of Trieste, Trieste, Italy

In modern neuroscience, therapeutic regenerative strategies (i.e., brain repair after damage) aim to guide and enhance the intrinsic capacity of the brain to reorganize by promoting plasticity mechanisms in a controlled fashion. Direct and specific interactions between synthetic materials and biological cell membranes may play a central role in this process and nerve tissue engineering has increasingly involved nanotechnology for the development of supermolecular architectures to sustain and promote neural regeneration following injury. The interaction between neurons and nanostructured materials is increasingly attracting interest, because it holds the potential of unexpected openings towards novel concepts for the design of smart devices based on nano(bio)materials properties. We used a multidisciplinary approach to investigate the impact of interfacing synthetic nanomaterials (carbon nanotubes) to neuronal networks.


FO-6:L04  High-density Implantable Microelectrode Arrays for Brain-machine Interface Applications
B. GHANE-MOTLAGH, M. SAWAN, Polystim Neurotechnologies Laboratory, Department of Electrical Engineering, Polytechnique Montreal, Montreal (Quebec), Canada 

Microelectrode arrays (MEAs) act as an interface between electronic circuits and neural tissues of implantable devices for recording signals from active neurons and selective electrical stimulation of a population of neurons. Biological response to chronic implantation of MEAs is an essential factor in determining a successful electrode design. By varying the geometries and material compositions of the arrays, fabrication techniques of MEAs insuring these electrode-tissue contacts try to obtain consistent recording signals from small groups of neurons without losing microstimulation capabilities. Finding appropriate coating materials which are biocompatible and improve electrical properties of MEAs is one of the main challenges. So far, none of these attempts have led to a major breakthrough. In this paper, we propose silicon-based high-density, three-dimensional (3D) electrode-tissue contacts MEAs. 3D tissue contacts of the electrodes in an array will provide more co ntacts between the electrodes and targeted neural tissue. More importantly, the novel geometry will allow not only recording from different depths of the brain but may provoke less tissue damage during insertion. Electrodes are coated with biocompatible nano-materials to improve both neural recording and stimulation.


FO-6:IL05  Regenerative Peripheral Nerve Interfacing of Smart Prosthetics
M. ROMERO-ORTEGA, University of Texas at Arlington, Arlington, TX, USA

Advanced robotic limbs are multi-fingered lightweight devices capable of up to 22 degrees of freedom. However, providing users with natural control and feel of such robotic limbs remains a formidable challenge. Peripheral nerves in the residual limbs of amputees offer a readily accessible portal to the bidirectional flow of information between the nervous system of the user, and smart robotic devices. To access such portal, several types of peripheral nerve interfaces have been developed along a spectrum of invasiveness and sensitivity. Regenerative Peripheral Interfaces (RPIs) rely in the spontaneous capability of the injured peripheral nerves to regenerate through electrode arrays, establishing a bidirectional connection between the transected nerves of amputees and smart robotic prosthetics. Despite the different types of multi-electrode RPIs, a number of challenges in electrode design and material selection remain. I will review emerging techniques that harness the molecular biology of nerve regeneration to develop electrode coating materials designed to reduce the foreign body response, and achieve long-term recordings, specific fiber recording, and sensory-modality stimulation, in order to develop reliable closed feedback loop neurointerfacing of peripheral nerves.


FO-6:IL06  Molecular Self-assembly of Peptide/Neural Cells Biointerfaces
S. YITZCHAIK, Institute of Chemistry, and the Center for Nanoscience and Nanotechnology, The Hebrew University of Jerusalem, Jerusalem, Israel

This contribution presents the use of self-assembled peptidic monolayers in bioelectronic hybrids including electronic coupling to neurons and biochemical sensing. The first part describes novel approach towards neuronal engulfment and the prospect towards intracellular recording. In the second part, we describe selectivity-sensitivity data in the kinase-promoted phosphorylation of peptidic substrates. These peptidic monolayers are investigated using electrochemical impedance spectroscopy (EIS) and square wave voltammetry (SWV) methods. EIS based sensor shows a remarkably high sensitivity and sequence specificity. Nanoscopic studies demonstrate a distinct disordering of the monolayer following phosphorylation, which can explain new signal amplification mechanism and high sensitivity for kinase-promoted phosphorylation. Enhanced sensitivity and faster response is demonstrated with the amperometric sensor (SWV). Finally, we demonstrated sensing capabilities towards kinase competitive inhibitors, which might prove useful for the development of high-throughput biosensor for anticancer drug leads.


FO-6:IL07  Flexible Optical and Electronic Platforms for Neural Recording, Interrogation and Repair
A. CANALES¹, XIAOTING JIA², A. LU¹, U. FRORIEP², P. ANIKEEVA^{1, 2}, ¹Department of Materials Science and Engineering, ²Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, MA, USA

Many neurological disorders are characterized by inhibited/amplified neural activity in a particular region of the nervous system or lack of communication between the two regions. Current approaches to treatment of these disorders are often based on drugs with undesirable side effects and limited terms of effectiveness, or on mechanically invasive and bulky electronic devices. Consequently, there is a pressing need for biocompatible materials and devices allowing for precise minimally invasive manipulation and monitoring of neural activity.
In my talk, I will illustrate how a fabrication process inspired by optical fiber production allows to create flexible multifunctional probes capable of optical, electronic and pharmacological interfaces with neural tissues in vivo. It will then be demonstrated how these fiber-inspired neural probes (FINPs) can be tailored to applications within a specific part of nervous system such as the brain or spinal cord. Finally, I will show recent applications of fiber-inspired fabrication for polymer-based optoelectronic neural scaffolds (OPTELS) - an electronically active platform for neural repair and optogenetic stimulation.

 
Session FO-7 - Progress in Implant Prosteses

FO-7:IL01  Electrochemically Deposited Calcium Phosphate Coatings for Orthopedic and Dental Implants
N. ELIAZ, Dept. Materials Science and Engineering, Tel-Aviv University, Ramat Aviv, Tel Aviv, Israel

In recent years, interest has evolved in electrochemically deposited hydroxyapatite (HAp) and other calcium phosphates as an alternative to the traditional plasma-sprayed (PS) process for coating of orthopedic and dental implants. Thus, we have deposited such coatings on commercially pure Ti and Ti-6Al-4V samples by cathodic polarization. The reaction kinetics was found to be controlled by charge transfer at the interface. As in the human body, HAp formed via transformation of a precursor phase (octacalcium phosphate). The effects of bath pH and temperature were studied experimentally, while a speciation-precipitation model was applied for understanding the effects of bath conditions. Corrosion tests confirm that the porous coatings did not introduce any localized corrosion issues. The effects of mechanical and chemical surface pre-treatments and a surface electron post-treatment on the adhesion strength, surface morphology, wettability, and interactions with bone-forming cells and bacteria were also studied. Animal studies were used to quantify osseointegration and evaluate the level of cracking compared to commercial PS coatings. The importance of coating solubility in vivo will be discussed. The coatings developed in the lab are currently being commercialized.


FO-7:IL02  Cortical-bone-mimetic Hierarchical Composites
E. JABBARI, Chemical Engineering Department, University of South Carolina, Columbia, SC, USA 

Materials and technologies that mimic the native nanostructure, organization, architecture, and complexity of the skeletal tissue hold great promise for creating synthetic substitutes for reconstruction of skeletal defects. The main approaches for creating synthetic substitutes are top-down and bottom-up. In the top-down approach, clinically relevant three-dimensional constructs are produced to fill large defects but the construct provides limited control over matrix organization at the micro-scale. The bottom-up approach provides flexibility in controlling spatial distribution of growth factors and cells and tissue architecture, but the assembly of small building blocks to a clinically relevant size is a challenge. I will discuss challenges to the synthesis of biomaterials for regeneration of load-bearing tissues with emphasis on merging nanomaterial synthesis with micro-scale assembly to create constructs that mimic the structure of osteons with balanced physiochemical, mechanical, and biological properties.


FO-7:L04  Mechanical Behaviour of Alumina Toughened Zirconia Nanocomposites with Different Alumina Additions  
L.A. DIAZ¹, S. RIVERA², A. FERNÁNDEZ¹, A. OKUNKOVA³, YU.G. VLADIMIROV³, R. TORRECILLAS^{1, 3}, ¹Centro de Investigación en Nanomateriales y Nanotecnología (CINN) Consejo Superior de Investigaciones Científicas (CSIC) - Universidad de Oviedo (UO) - Principado de Asturias (PA), Llanera, Asturias, Spain; ²Nanoker Research, S.L., Polígono de Olloniego, Oviedo, Asturias, Spain; ³Moscow State University of Technology "STANKIN", Moscow, Moscow Oblast, Russian Federation

Zirconia (Y-TZP) and alumina are monolithic ceramics used today in a wide variety of structural components. However, both materials present important drawbacks for some specific applications in the biomedical and dental field. In the case of alumina, its moderate strength (500 MPa) and toughness (4 MPa.√m) makes it unsuitable for high loading conditions. On the other hand, zirconia presents higher strength and toughness values (900 MPa and 6 MPa.√m) than alumina but it is a material limited in its long-term behaviour due to its bad response to hydrothermal ageing and a pronounced tendency for subcritical crack growth.
Due to this fact, ceramic nanocomposites made of alumina and zirconia (ATZ and ZTA) have been developed in the last years in order to overcome the main drawbacks of the monolithic materials as they can combine the properties of both, strong and tough materials, simultaneously, with null ageing and even higher biocompatibility. In this work, several amounts of alumina disperse phase (15, 35 and 50 vol %) were added to two different zirconia matrices (Y2O3 - 3 mol % and CeO2 - 10 mol %) in order to see their effect on the mechanical properties, subcritical crack propagation and long-term reliability.
 
 
Poster Presentations

FO:P02  Bacterial Detection Based on the T7 Virus-nanoparticle Complexes
JONG-WOOK LEE, GUN HYUK JANG, KWAN HYI LEE, Center for Biomaterials, KIST Biomedical Research Institute, Seoul, Republic of Korea; Department of Biomedical Engineering, University of Science and Technology (UST), Seoul, Republic of Korea 

Bacteriophages are traditionally used for the development of phage display technology. Recently, their nano-sized dimensions and ease with which genetic modifications can be made to their structure/function have put them in the spotlight towards use in a variety of biosensors. In particular, the expression of any protein or peptide on the extraluminal surface of bacteriophages is possible by genetically engineering the genome.
T7 bacteriophage, which is an icosahedral phage, is largely composed of two segments: a capsid and a tail fiber region. We modified T7 bacteriophages by expressing biotinylated peptide on the capsid for subsequent binding to streptavidin-coated nanoparticles. T7-nanoparticle complexes as biosensors immobilize bacteria via their tail fiber region. T7 nanocoplexes, which have been conjugated with fluorescent nanoparticles on their head, also generate a fluorescence signal on the detection of bacteria. In this study, we have demonstrated that the number of bacteria can be quantitatively assayed with high-sensitivity.


FO:P03  Synthesis of Bioglass-ceramic by Sol-gel Method for Medical Application
P. ESLAMI, G. BALDI, Ce.Ri.Col Research Center of Colorobbia, Sovigliana Vinci, Italy

The continuous application of implants and prosthesis requires increased research efforts regarding optimization of their properties and functionality. A possibility to enhance the performance of metallic implants, in particular the bonding to bone tissue, is to coat them with bioactive layers; therefore, the most importnat function of this coating is to increase corrosion resistance of implant and to make the surface more bioactive to improve implant fixation to bone tissue.Consequently, selected BG should have excellent biocompatibility and high mechanical strength. As a result, regarding to sol-gel processed BG that has better compositional control with significant bioactivity, we motivated to design, synthesize, and characterize novel bioglass-ceramic %48.6 SiO2-%4.2Na2O- %23.5CaO-%2.7MgO-%12.2-P2O5-%8.8TCP by sol-gel method, followed by sintering at 750 oC for 2h so that it could be applied as a bioactive coating for Ti implant.Bioactivity was considered by soaking samples in SBF solution at 37 oC for 3,7, 14, and 21 days. Precipitation of nanocrystallin HA on the surface of BGC after soaking in SBF was considered by SEM, XRD, and EDS. Results revealed a tick and well-formed apatite on the surface of BG with a molar Ca/P ratio of 1.96 that presents highly bioactive behaviour.

 
FO:P04  Characterization and Biocompatibility Evaluation of Hydroxyapatite Doped with Silver and/or Fluorine
V. GONZALEZ-TORRES, E.R. MÉNDEZ, Centro de Ciencias de la Salud Unidad Valle de las Palmas UABC, Tijuana, Baja California, México; L.A. GAITÁN-CEPEDA, Facultad de Odontología UNAM, México; M.E. TORRES-ARELLANO, Facultad de Odontología Tijuana UABC, Tijuana, Baja California, México; C. DÍAZ-TRUJILLO, Facultad de Ciencias Químicas e Ingeniería UABC, Tijuana, Baja California, México 

Hydroxyapatite [Ca5(PO4)3(OH)] is a form of calcium phosphate inorganic compound of great importance in health area because of its presence in bones as in teeth where it provides structural rigidity to the matrix. Hydroxyapatite is often used in the biomaterial area as a primary material for implants that help regenerate tissues. The addition of doping agents may improve the degree of crystallization providing new characteristics to the material without losing its biocompatibility. The present study shows characterization results for a hydroxyapatite biomaterial doped with silver and/or fluorine prepared throw combustion method. The mineralogy was determined using X-ray diffraction identifying the following phases: Ca5(PO4)3(OH), Ca2P2O7, Ag3PO4 and Ca3(PO4)2; morphologic structure was studied by scanning electron microscopy, biocompatibility tests through intramuscular and subcutaneous implantation were performed in rodents to evaluate inflammatory response at 7, 14 and 30 days.


FO:P06  Fluorescent Dendron-CD Nanotubes for Biosensory Platform
JEONGHUN LEE, DOOHONG MIN, CHULHEE KIM, Department of Polymer Science and Engineering, Inha University, Incheon, Korea

The supramolecular fluorescent dendron nanotubes of which the surface is covered with cyclodextrins (CDs)were constructed by a self-assembly approach. In particular, their bisensory characterisctics will be discussed.
The organic nanotubes with unique fluorescence characteristics were fabricated by self-assembly of the amide dendrons and cyclodextrins (CDs). The surface of the nanotube is covered with CDs. Therefore, the functional group on the surface of the nanotube is controlled precisely by modifying the functionality of CD. In addition, the fluorescence properties of the nanotubes are highly dependent on the exterior environment of the nanotube. The facile introduction of specific peptide epitopes for specific binding of biomolecules gives rise to high selectivity for the nanotube. Therefore, the dendron-CD nanotube provides a uniuqe opportunity for biosensory application. We wil discuss the biosensory properties of the nanotubes for proteins, sugars and ions. The dnedron-CD nanotubes can be utilized as an efficient biosensory platform.


FO:P08  Coating of Hydroxyapatite on the Surface-modified Polyetheretherketone
N. SUZUKI¹, T. UMEDA¹, H. KUWAHARA¹, Y. MUSHA², K. ITATANI¹, ¹Department of Materials and Life Sciences, Sophia University, Tokyo, Japan; ²2nd Department of Orthopaedic Surgery, Toho University, Tokyo, Japan

The conditions for the coating of hydroxyapatite (Ca10(PO4)6(OH)2;HAp) on polyetheretherketone (PEEK) were investigated in order to fabricate  medical devices, e.g., vertebra spacer with excellent biocompatibility. The treatment of PEEK by acetic acid was conducted to form hydroxyl group to change surface properties from hydrophobic to hydrophilic. Further, the conditions to coat HAp on PEEK substrate were examined by (i) the immersion into calcium-phosphate solution prepared by bubbling CO2 gas into HAp-suspension solution, and then (ii) microwave or hydrothermal heating at 100ºC. The immersion of PEEK into the calcium phosphate solution and microwave heating were effective in coating by HAp. The formation of plate-like HAp on the surfaces of acid-treated PEEK could be encouraged by the microwave heating. The analytical results obtained by energy-dispersive X-ray microanalysis showed that the calcium/phosphorus ratio was 1.643 or close to the stoichiometric value of HAp (1.667). It is found from the above results that the larger amount of HAp could be effectively formed on the acetic acid-treated PEEK by the microwave heating.


FO:P11  Residual Thermal Stress of Spinel Based-ceramic Infiltrated with Glass Rich in Lanthanum
P. CIPRIANO DA SILVA¹, C. DOS SANTOS^{1, 2}, ¹Unifoa Centro Universitario de Volta Redonda, Volta Redonda, RJ, Brazil; ²UERJ- FAT, Brazil

Ceramic composites developed for glass infiltration in ceramic substract has as main advantage the reduction of fabrication temperatures of ceramic parts compared to the solid state sintering. In this work, spinel based-ceramics infiltrated with glass rich in Lanthanum, aiming applications in dental ceramics, were developed and studied. Pre-sintered spinell substrates with porosity 10, 15 and 20% were infiltrated with glass at temperature 1120°C-120min, using heating and cooling rate of 10°C/min. The composites present relative density superior 99% in every investigated condition, and X-ray diffraction indicated the phase MgAl2O4, as unique crystalline phase detected. Hardness Vickers varying between 850-1000HV and fracture toughness varying between 3.0 to 5.0MPa.m1/2 were obtained for composites with variation of intergranular phase quantity. The evaluation of residual thermal stress indicates that compressive thermal stress are generated in every composition varying from 70-90MPa, for compositions containing between 10 to 20% of infiltrated glass, respectively. Theoretical calculations indicate that the excellent quantity of inter-granular phase infiltrated must be 17%, for obtaining better resistance to crack propagation in this material.