FQ - 13th International Conference
Advanced Biomaterials and Nano-biotechnology for Medicine


FQ:KL  Coming to Age with Nanomedicine: Progress and Disappointments Over the Past 30 Years
T.J. Webster, CSA, Interstellar Therapeutics, USA; Professor, Vellore Institute of Technology, India and Hebei University of Technology, China

Without a doubt, nanotechnology has revolutionized numerous fields, including medicine. What started as an idea that smaller nanoparticles, greater roughness at the nanoscale, and electrically active nanotubes could improve disease prevention, detection and treatment, has turned into a mature field with numerous FDA approved implants. We, as a community, have learned that nanoparticles can avoid immune system clearance to prolong drug release and can be functionalized with biomolecules to target not just cell membrane receptors but also intracellular components to control or kill cancer cells, inhibit bacteria function, and improve tissue growth. We have also learned how to make implantable nanosensors that can survey the body and treat diseases on-demand. Moreover, regulatory agencies have approved nanotextured surface features that can (without a change in chemistry) improve implant lifetimes. Despite these advances and others, the field still suffers from a lack of knowledge of toxicity, manufacturability, how to assemble nanoparticles into larger structures and more. This talk will cover the most significant advancements nanomedicine has made throughout the year and highlight where knowledge is still needed.

FQ-1:IL03  The Processing and Application of Controlled Porous Bioceramic Materials Based on Calcium Phosphates Doped with Different Cations
Dj. Veljovic, R. Petrovic, Dj. Janackovic, Faculty of Technology and Metallurgy, University of Belgrade, Belgrade, Serbia; V. Ugrinovic, T. Matic, Innovation Center of the Faculty of Technology and Metallurgy, University of Belgrade, Belgrade, Serbia

Calcium phosphate minerals as the dominant inorganic constituents of human bones and teeth have the central part of the research of novel bioceramic materials. This study was focused on the processing and application of controlled macro-porous templates for bone tissue formation and micro-porous dentine substitutes, starting from meso-porous nanosized hydroxyapatite (HAp) multi-doped with Sr, Mg, Cu and Zn cations. Hydrothermally doped spherically agglomerated HAp nanosized powders were firstly calcinated in order to control morphology and phase transformation in more bioactive phases. Multi-doped calcinated powders were starting material for sintering of macro-porous bioceramic scaffolds. The optimization of scaffold processing and additionally strengthened with biodegradable polymeric coatings was investigated. The possibility for synthesis of macro-porous templates based on biodegradable double network hydrogels and doped calcinated fillers was also investigated. In both cases bioactive, biocompatible and osteoconductive macro-porous templates, with adequate mechanical properties for bone tissue engineering were processed. In the third part, controlled porous dental inserts were processed by sintering of doped HAp particles, with fracture toughness similar as human dentin.

FQ-1:L06  Physicochemical Study of a Calcium Carbonate-chitosan Composite Cement as a Potential Bone Substitute Material
E. TOUFIK1, 2, 3, H. Noukrati2, C. Rey4, H. Ben youcef1, A. Barroug2, 3, C. Combes4, 1Mohammed VI Polytechnic University (UM6P), HTMR-Lab, Benguerir, Morocco; 2Mohammed VI Polytechnic University (UM6P), High Institute of Biological and Paramedical Sciences, ISSB-P, Benguerir, Morocco; 3Cadi Ayyad University, Faculty of Sciences Semlalia, Marrakech, Morocco; 4CIRIMAT, Université de Toulouse, CNRS, Toulouse INP-ENSIACET, Toulouse, France

In the field of bone substitution, there is a growing interest in injectable materials able to be implanted by minimally invasive surgery. We aim to prepare and characterize self-setting composites based on a calcium carbonate cement and its association with chitosan in order to control cement resorption and injectability. Amorphous calcium carbonate and vaterite powders were synthesized by double decomposition process and then mixed with an acetic acid solution including different amounts of low Mw chitosan (DDa:75-85%) leading to hardened composites at 37°C. The composition, microstructure, injectability and mechanical properties of the composites were characterized using complementary techniques (XRD, FTIR spectroscopy, SEM, setting time measurements, injectability and compressive strength). We showed that all the cements were mainly composed of aragonite, a bioactive and resorbable phase of CaCO3. The formulation including 3.5% w/w chitosan showed a compromise between a good paste injectability (85%), appropriate setting time (a three-fold reduction of the setting time: 45 min), and enhanced compressive strength and ductility compared to those of the reference cement (no chitosan). We are now evaluating the in vitro bioactivity of these promising composites.

FQ-1:IL11  Isothermal Shape Change by Enzymatic Trigger
P.T. Mather, Penn State University, University Park, PA, USA; J.H. Henderson, S.L. Buffington, Syracuse University, USA

Shape memory polymers (SMPs) have great potential and multiple successes for utilization in medical devices and as tissue engineering platforms. Thus, cytocompatible shape memory polymers that are activated to change shape by either heat or light are being actively studied in basic and translational research. By comparison with those traditional activation methods, SMPs that are triggered directly by biological activity have not been reported. Recently, we developed and studied an enzymatically triggered shape memory polymer blend prepared by dual electropspinning that changes its shape isothermally in response to enzymatic activity. In particular, we selected a fixing phase that was enzymatically labile so that the temporary shapes – held in place by the labile fixing phase – transformed to permanent shape as a bioinert elastic (memory) phase was liberated to exert its stress. In this presentation we will describe such enzymatic recovery using bulk enzymatic degradation experiments and show that near-complete shape recovery is achieved by degradation of the shape-fixing phase and that the materials and shape recovery process are both cytocompatible. Finally, future research and application ideas will be described.

FQ-1:IL12  Growing Integration Layer [GIL] Strategy for Bio-active Ceramic Coating on Metallic Alloys
MASAHIRO YOSHIMURA1, 2, Chi-Huang HUANG1, 1Hi-GEM & PCGMR, Materials Science and Engineering, National Cheng Kung University, Tainan, Taiwan; 2Tokyo Institute of Technology, Tokyo, Japan

After long studies on bulk ceramic materials based on Zirconia, Apatite,etc. To overcome their intrinsic brittleness, we have considered Coatings of ceramics film(s) on other materials like metallic alloys etc., In 2008 we have proposed a novel concept and technology of “Growing Integration Layer” [GIL] method, where GIL(s) can be prepared via integration of ceramic film formation from a component of the alloys by chemical and /or electrochemical reactions in a solution at low temperature of RT-200℃. They have particular features: 1) Widely diffused interface(s), 2) Continuously graded layers grown from the bulk (substrate), 3) Low temperature process, etc. They are quite different from Integration so-called Layer-by-Layer [LBL] strategy, where every layer is deposited from the Top-by-top.
BaTiO3 or SrTiO3/TiOx GIL films on Ti plates formed by hydrothermal-electrochemical method since 1989 showed good adhesion. CaTiO3/Al2O3/Ti2Al GIL films on TiAl exhibited excellent adhesion and anti-oxidation performances. On a Ti-base Bulk Metallic Glass, we could succeed to prepare bioactive titanate nano-mesh layer by hydrothermal-electrochemical techniques at 90-120℃.
The GIL method can be applicable for wide variety of applications like thermal barrier, mechanical parts, environmental and/or chemical coating, conducting and or insulating films, biological and/or medical coating, etc., Particularly, GIL Bio-active coating on alloys would be one of the best examples. Please note that almost materials in bio-systems have been prepared via similar ways of GIL in a solution under ambient temperature and pressure conditions. Furthermore, we can make carbon films with various nanostructures on metal carbides by “reverse integration”.
1) M. Yoshimura et al., Mater. Sci. Eng. B,148,2-6(2008), 2) N. Sugiyama, M. Yoshimura et al., Acta Biomaterialia,5,1367-1373(2009), Mater. Sci. Eng. B,161,31-35(2009)
2) J-J. Wu,W-P. Liao and M. Yoshimura, Nano Energy 2(6),1354(2013)
3) J. Senthilnathan, M. Yoshimura et al., Carbon, 71,181-187 (2014)
4) C-H. Huang, M. Yoshimura et al. J. Chem. Phys C, accepting (2017)
5) C-H. Huang, M. Yoshimura et al..,Scientific Reports,submitted (2019)

FQ-1:L14  Spark Plasma Sintering, Crystallization, Mechanical Properties and Biological Behavior of an Innovative SrO- and MgO-containing Bioactive Glass
D. ANGIONI, R. Orrù, G. Cao, Dipartimento di Ingegneria Meccanica, Chimica e dei Materiali, Università degli Studi di Cagliari, Cagliari, Italy; S. Garroni, A. Iacomini, Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, Sassari, Italy; D. Bellucci, V. Cannillo, Dipartimento di Ingegneria “Enzo Ferrari”, Università di Modena e Reggio Emilia, Modena, Italy

The recently developed BGMS10 bioactive glass (47.2 SiO2, 25.6 CaO, 10.0 MgO, 10.0 SrO, 2.3 Na2O, 2.3 K2O, and 2.6 P2O5, mol.%) exhibits a low tendency to crystallize, as confirmed by the corresponding high effective activation energy (538.9 kJ/mol) compared to standard 45S5Bioglass® (230-338 kJ/mol) and S53P4 (283-311 kJ/mol) glasses, all determined using the Kissinger method. The use of Spark Plasma Sintering (SPS) provides nearly fully dense (99.7 %) and completely amorphous products at 750°C. On the other hand, the incipient crystallization from the parent glass is observed at dwell temperature (TD) of 850°C, while 95 wt. % crystallized samples are obtained at 950°C. The corresponding crystalline phases are α-CaSiO3, and β-CaSiO3, with grain size of 89 and 97 nm, respectively. Young’s modulus of bulk samples is found to increase from 90.9 to 98.4 GPa as a consequence of crystallization occurrence. However, the measured values of Vickers hardness are higher (718.8) for partially crystallized samples (TD=850°C) compared to nearly full crystallized ones (619.8), which show lower density (98.6%). Biological tests in SBF indicate that the formation of the silica-gel film, which precedes apatite nucleation, is observed to take primarily place on the amorphous region of substrate.

FQ-1:L16  Diatomite-based Nanocarriers for the Sustained Release of Galunisertib in Colorectal Cancer Cells
C. TRAMONTANO1, 2, G. Chianese1, L. De Stefano1, I. Rea1, E. Lonardo3, D. delle Cave3, 1Institute of Applied Science and Intelligent Systems (ISASI), National Research Council of Naples, Naples, Italy; 2Department of Pharmacy, University of Naples Federico II, Naples, Italy; 3Institute of Genetics and Biophysics (IGB), National Research Council of Naples, Naples, Italy

The design of biomaterials for medical use has followed the progress in engineering, chemistry, pharmaceutics, and medicinal fields. Biomaterials have contributed to the development of innovative strategies to treat a range of diseases, including cancer. Many of these materials have been used as drug delivery systems to release therapeutic agents to the target site within the body, improving patient compliance and quality of life. Research in the field of biomaterials for controlled drug delivery gave rise to the design of organic and inorganic nanoparticles (NPs), among which porous silica NPs have revolutionized the field of modern medicine. In this work, we engineered the surface of diatomite nanoparticles (DNPs) to deliver the small molecule Galunisertib to colorectal cancer cells (CRC)1. Diatomite is a sedimentary rock originated by diatom skeletons mainly formed by amorphous mesoporous silica, which has been approved by the Food and Drug Administration2. We modified the surface of DNPs with gold nanoparticles and entrapped Galunisertib in the siliceous structure surrounded by a layer of crosslinked gelatin. The biodegradable gelatin layer enabled a sustained release of the drug to CRC up to 48 hours, with a therapeutic effect exceeding the free drug and with lower toxicity.

FQ-3:IL01  Smart Stimuli-sensitive Combination Nanopreparations: Next Generation of Drug Delivery Systems
V.P. Torchilin, Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, USA

Tumor therapy, especially in the case of multidrug resistant cancers, could be significantly enhanced by using siRNA down-regulating the production of proteins, which are involved in cancer cell resistance, such as Pgp or survivin. Even better response could be achieved is such siRNA could be delivered to tumors together with chemotherapeutic agent. This task is complicated by low stability of siRNA in biological surrounding. Thus, the delivery system should simultaneously protect siRNA from degradation. We have developed several types of lipid-core polymeric micelles based on PEG-phospholipid or PEI-phospholipid conjugates, which are biologically inert, demonstrate prolonged circulation in the blood and can firmly bind non-modified or reversibly-modified siRNA. Additionally, these nanopreparations can be loaded into their lipidic core with poorly water soluble chemotherapeutic agents, such as paclitaxel or camptothecin. In experiments with cancer cell monolayers, cancer cell 3D spheroids, and in animals with implanted tumors, it was shown that such co-loaded preparations can significantly down-regulate target proteins in cancer cells, enhance drug activity, and reverse multidrug resistance. In order to specifically unload such nanopreparations inside tumors, we made them sensitive to local tumor-specific stimuli, such as lowered pH, hypoxia, or overexpressed certain enzymes, such as matrix metalloproteases. Using pH-, hypoxia-, or MMP2-sensitive bonds between different components of nanopreparations co-loaded with siRNA and drugs, we were able to make the systems specifically delivering biologically active agents in tumors, which resulted in significantly improved therapeutic response.

FQ-3:IL04  Intelligent Release of Functional Molecules Encapsulated in Complex Electrospun Polymer Fibers for Chem/Bio/Medical Applications
A.J. Steckl, D. Han, S. Tort, University of Cincinnati, Cincinnati, OH, USA

An important direction in materials research for chemical, biological and medical applications is the development of novel materials platforms for the controlled (“intelligent”) release of functional molecules encapsulated in the platform. Controlling the release of one or more encapsulated molecules in response to external stimuli such that they can be delivered with a specified quantity vs time profile is the essence of intelligent release. Complex fiber formation using the electrospinning method has enabled the production of a large variety of materials with extremely high surface to volume ratio. In this paper, we review approaches for intelligent release of functional molecules encapsulated in electrospun fiber membranes for various applications. This includes the electrospinning method (single nozzle, twin nozzle, coaxial), fiber properties (homogenous, core-sheath, etc.), encapsulated molecules (drugs, enzymes, protein, bacteria), release mechanism (temperature, pH, solvent), release kinetics (burst, triggered, delayed), and chem/bio/med applications (tissue repair, anti-microbial, GI tract release). The presentation concludes with a look ahead at the future promise and challenges of electrospinning fiber membranes for intelligent release of functional molecules.

FQ-4:IL01  Multifunctional Bioceramics and Glasses for Advanced Therapy and Theranostics
F. BAINO, Institute of Materials Physics and Engineering, Applied Science and Technology Department, Politecnico di Torino, Torino, Italy

Multifunctional biomaterials eliciting multiple therapeutic effects simultaneously hold the potential to revolutionize future disease management. These properties are highly appealing in many biomedical applications, including cancer treatment. In this regard, over the last 15 years, there has been a growing interest in the engineering of various kinds of theranostic nanoparticles for simultaneous cancer imaging and therapy. Specifically. nano-scale bioceramics and glasses (e.g. mesoporous materials) have become a powerful tool not only as carrier of chemotherapeutic drugs but also as imaging contrast agents that provide valuable information about the state of the disease and its progression. Additionally, the possibility to design stimuli-responsive nano-platforms able to release their payload in response to specific stimuli allows improving the control on the administered dosage. Here we will discuss the current status and future perspectives of multifunctional bioceramics and bioactive glasses, with special focus on nano-systems and theranostic applications for tumor management.

FQ-4:L02  Theranostic Copper Oxide Nanoparticles Loaded Polymeric Nanocarriers as a Promising Drug Delivery System
I.S. WEITZ, Department of Biotechnology Engineering, ORT Braude College, Karmiel, Israel

Cancer tumor treatment is still a major clinical challenge. Copper oxide nanoparticles (CuO NPs) is a promising candidate in cancer nanomedicine due to their inherent multifunctional capabilities. However, high dose of CuO NPs can induce severe toxicity in tumor microenvironment. Thus, introducing stimuli-responsive agent to CuO NPs-based polymeric carrier is a crucial step for controlled drug delivery applications. The present work addresses the above challenges by encapsulation of CuO NPs within poly(lactic-co-glycolic acid) nanospheres that are coated further by thin layers of polydopamine and poly(ethylene glycol). Various analytical measurements were performed to characterize the coated nanospheres in terms of particle size, morphology and composition. In addition, their application as contrast agent was evaluated by magnetic resonance imaging. Upon irradiation with laser sources in the NIR range, effective and rapid copper release from the coated nanospheres and a potent anti-tumor efficacy in head and neck cancer cell line, were demonstrated. This Heating efficiency was higher by 85% in comparison to uncoated nanospheres and hence can provide much-reduced collateral damage to healthy tissues surrounding the target.

FQ-5:IL01  Clinical Translation in Regenerative Engineering
C.T. Laurencin, Connecticut Convergence Institute for Translation in Regenerative Engineering, University of Connecticut, Health Center Farmington, CT, USA

We define Regenerative Engineering as a Convergence of Advanced Materials Science, Stem Cell Science, Physics, Developmental Biology, and Clinical Translation. Our focus has been musculoskeletal tissue regeneration and involves a transdisciplinary approach. Polymeric nanofiber systems create the prospect for biomimetics that recapitulate connective tissue ultrastructure allowing for the design of biomechanically functional matrices, or next generation matrices that create a niche for stem cell activity. Polymer and polymer-ceramic systems can be utilized for the regeneration of bone. Hybrid matrices possessing micro and nano architecture can create advantageous systems for regeneration, while the use of classic principles of materials science and engineering can lead to the development of three dimensional systems suitable for functional regeneration of tissues of the knee. Engineered systems for soft tissues take advantage of architectural, biomechanical and biochemical cues. Principles found in embryological development and in developmental morphogenesis will ultimately be critical for addressing grand challenges in regeneration. Drug Delivery approaches utilize conventional and unconventional concepts. Through convergence of a number of technologies, we can approach translational regeneration in a more holestic way.


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