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Publications in this journal

• The cohesive behavior of soft biological "glues": Experiments and modeling.

  Authors: A Khayer Dastjerdi, M Pagano, M T Kaartinen, M D McKee, F Barthelat

  Acta biomaterialia.

  Extracellular proteins play a key role in generating and maintaining cohesion and adhesion in biological tissues. These "natural glues" are involved in vital biological processes such as bloodExtracellular proteins play a key role in generating and maintaining cohesion and adhesion in biological tissues. These "natural glues" are involved in vital biological processes such as blood clotting, wound healing and maintaining the structural integrity of tissues. Macromolecular assemblies of proteins can be functionally stabilized in a variety of ways in situ that include ionic interactions as well as covalent crosslinking to form protein networks that can extend both within and between tissues. Within tissues, myriad cohesive forces are required to preserve tissue integrity and function, as are additional appropriate adhesive forces at interfaces both within and between tissues of differing composition. While the mechanics of some key structural adhesive proteins have been characterized in tensile experiments at both the macroscopic and single protein levels, the fracture toughness of thin proteinaceous interfaces has never been directly measured. Here, we describe a novel and simple approach to measure the cohesive behavior and toughness of thin layers of proteinaceous adhesives. The test is based on the standard double-cantilever beam test used for engineering adhesives, which was adapted to take into account the high compliance of the interface compared to the beams. This new "rigid double-cantilever beam" (RDCB) method enables stable crack propagation through an interfacial protein layer, and provides a direct way to measure its full traction-separation curve. The method does not require any assumption for the shape of the cohesive law, and the results provide abundant information contributing to understanding the structural, chemical and molecular mechanisms acting in biological adhesion. As an example, we present results using this method for thin films of fibrin - a protein involved in blood clotting and used clinically as a tissue bio-adhesive after surgery - with the effects of calcium and crosslinking by Factor XIII being examined. Finally, a simple model is proposed demonstrating how a bell-shaped cohesive law forms during the failure of the fibrin interface based on an eight-chain model whose structure degrades and changes configuration with stress.2.

• The microRNA expression signature on modified titanium implant surfaces influences genetic mechanisms leading to osteogenic differentiation.

  Authors: Nishant Chakravorty, Saso Ivanovski, Indira Prasadam, Ross Crawford, Adekunle Oloyede, Yin Xiao

  Acta biomaterialia.

  Topographically and chemically modified titanium implants are recognized to have improved osteogenic properties, however the molecular regulation of this process remains unknown. This study aimed toTopographically and chemically modified titanium implants are recognized to have improved osteogenic properties, however the molecular regulation of this process remains unknown. This study aimed to determine the microRNA profile and the potential regulation of osteogenic differentiation following early exposure of osteoprogenitor cells to sand-blasted, large-grit acid-etched (SLA) and hydrophilic SLA (modSLA) surfaces. Firstly, the osteogenic characteristics of the primary osteoprogenitor cells were confirmed using ALP activity and Alizarin Red S staining. The effect of smooth (SMO), SLA and modSLA surfaces on the TGF-β/BMP (BMP2, BMP6, ACVR1) and non-canonical WNT/Ca(2+) (WNT5A, FZD6) pathways, as well as the integrins ITGB1 and ITGA2 was determined. It was revealed that the modified titanium surfaces could induce the activation of TGF-β/BMP and non canonical WNT/Ca(2+) signaling genes. The expression pattern of microRNAs (miRNAs) related to cell differentiation was evaluated. Target predictions for the differentially regulated miRNAs indicated that 35 and 32 miRNAs were down-regulated on the modSLA and SLA surfaces respectively, when compared with smooth surface (SMO). 31 miRNAs that were down-regulated were common to both modSLA and SLA. There were 10 miRNAs up-regulated on modSLA and 9 on SLA surfaces, amongst which 8 were the same as observed on modSLA. TargetScan predictions for the down-regulated miRNAs revealed genes of the TGF-β/BMP and non-canonical Wnt/Ca(2+) pathways as targets. This study demonstrated that modified titanium implant surfaces induce differential regulation of miRNAs, which potentially regulate the TGF-β/BMP and WNT/Ca(2+) pathways during osteogenic differentiation on modified titanium implant surfaces.

• Corneal reinforcement using an acellular dermal matrix for an analysis of biocompatibility, mechanical properties, and transparency.

  Authors: Ziyuan Liu, Jing Ji, Jing Zhang, Chen Huang, Zhaojun Meng, Weiqiang Qiu, Xuemin Li, Wei Wang

  Acta biomaterialia.

  The aim of this study was to analyze the viability of using an acellular dermal matrix (ADM) as a reinforcement material for peripheral corneal thinning disease. The complete removal of cellThe aim of this study was to analyze the viability of using an acellular dermal matrix (ADM) as a reinforcement material for peripheral corneal thinning disease. The complete removal of cell components was confirmed by hematoxylin and eosin (H&E) and 4',6-diamidino-2-phenylindole (DAPI)staining. Transmission electron microscopy determined that the stromal structure was well preserved. Uniaxial tests revealed that the ADM had strong mechanical properties. After being implanted into rabbit cornea, the ADM showed no sign of rejection and even achieved good transparency 24 weeks post surgery. H&E staining demonstrated that keratocytes grew in the ADM and the ADM/cornea interface became blurry. Picrosirius red staining revealed great changes of the collagen in the ADM. Uniaxial testing of the reinforced cornea showed better mechanical strength than the normal rabbit cornea, but this did not exhibit statistical significance. These results suggest that ADM is a worthy candidate for the future exploration of reinforcement material for peripheral corneal thinning problems.

• Bulk properties and bioactivity assessment of porous polymethylmethacrylate cement loaded with calcium phosphates under simulated physiological conditions.

  Authors: M A Lopez-Heredia, Y Sa, P Salmon, J R de Wijn, J G C Wolke, J A Jansen

  Acta biomaterialia.

  Polymethylmethacrylate (PMMA) cements are amply used in spinal surgery. Nevertheless, these type of cements present some documented drawbacks. Efforts are made to improve the properties andPolymethylmethacrylate (PMMA) cements are amply used in spinal surgery. Nevertheless, these type of cements present some documented drawbacks. Efforts are made to improve the properties and biological performance of solid PMMA. A porous structure would seem to be advantageous for anchoring purposes. This work studied the bulk physicochemical, mechanical and interconnectivity properties of porous PMMA cements loaded with several percentages of calcium phosphate (CaP). As a measure of bioactivity, changes of PMMA cements under simulated physiological conditions were studied in a calcium phosphate solution for 0, 3, 7, 14, 21 and 28 days. Scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), micro-computed tomography (μ-CT) and mechanical compression tests were performed to characterize the morphology, crystallographic and chemical composition, interconnectivity and mechanical properties, respectively. SEM allowed observing the result of loading CaP into the porous PMMA, which was corroborated by XRD, FTIR and μ-CT. No interference of the CaP with the PMMA was detected. μ-CT described similar interconnectivity and pore distribution for all CaP percentages. Mechanical properties were not significantly altered by the CaP percentages or the immersion time. Hence, porous PMMA was effectively loaded with CaP, which provided the material with properties for potential osteoconductivity.

• Crosslinking and composition influence the surface properties, mechanical stiffness and cell reactivity of collagen-based films.

  Authors: Chloe N Grover, Jessica H Gwynne, Nicholas Pugh, Samir Hamaia, Richard W Farndale, Serena M Best, Ruth E Cameron

  Acta biomaterialia.

  This study focuses on determining the effect of varying the composition and crosslinking of collagen-based films on their physical properties and interaction with myoblasts. Films composed ofThis study focuses on determining the effect of varying the composition and crosslinking of collagen-based films on their physical properties and interaction with myoblasts. Films composed of collagen or gelatin and crosslinked with a carbodiimide were assessed for their surface roughness and stiffness. These samples are significant because they allow variation of physical properties as well as offering different recognition motifs for cell binding. Cell reactivity was determined by the ability of myoblastic C2C12 and C2C12-α2+ cell lines (with different integrin expression) to adhere to and spread on the films. Significantly, crosslinking reduced the cell reactivity of all films, irrespective of their initial composition, stiffness or roughness. Crosslinking resulted in a dramatic increase in the stiffness of the collagen film and also tended to reduce the roughness of the films (R(q)=0.417±0.035μm, E=31±4.4MPa). Gelatin films were generally smoother and more compliant than comparable collagen films (R(q)=7.9 ±1.5nm, E=15±3.1MPa). The adhesion of α2-positive cells was enhanced relative to the parental C2C12 cells on collagen compared with gelatin films. These results indicate that the detrimental effect of crosslinking on cell response may be due to the altered physical properties of the films as well as a reduction in the number of available cell binding sites. Hence, although crosslinking can be used to enhance the mechanical stiffness and reduce the roughness of films, it reduces their capacity to support cell activity and could potentially limit the effectiveness of the collagen-based films and scaffolds.

• Inhibitory Effects of Luteolin on Titanium-Particle-Induced Osteolysis in a Mouse Model.

  Authors: Dong-Kyu Shin, Mi-Hyung Kim, Sang-Han Lee, Tae-Ho Kim, Shin-Yoon Kim

  Acta biomaterialia.

  Wear particles liberated from the surfaces of an implanted prosthesis are associated with peri-implant osteolysis and subsequent aseptic loosening. In the latter, wear-particle-induced inflammationWear particles liberated from the surfaces of an implanted prosthesis are associated with peri-implant osteolysis and subsequent aseptic loosening. In the latter, wear-particle-induced inflammation and osteoclastogenesis have been identified as critical factors, and their inhibition as important steps in the treatment of affected patients such as those undergoing total hip replacement. In this study, the ability of luteolin to inhibit both titanium (Ti)-particle-induced osteoclastogenesis in vitro and osteolysis in a murine calvaria Ti-particle-induced model of osteolysis was examined. The results showed that luteolin, a highly potent and efficient inhibitor of TNF-α and interleukin-6 expression, inhibited Ti-particle-induced inflammatory cytokine release, osteoclastogenesis, and bone resorption in bone marrow macrophages. In the murine calvarial model of osteolysis, microcomputed tomography and histological analyses showed that the Ti particles caused significant bone resorption and increased TRAP (+) multinuclear osteoclasts whereas this was not the case in the luteolin treatment group, in which osteolytic suppression was accompanied by a decrease in both TNF-α production and serum levels of the osteoclastic marker CTX. These results support the use of luteolin as a natural compound in the prevention and treatment of aseptic loosening after total replacement arthroplasty.

• Spatial orientation of collagen fibers in the Abdominal Aortic Aneurysm's wall and its relation to wall mechanics.

  Authors: T Christian Gasser, Sara Gallinetti, Xiao Xing, Caroline Forsell, Jesper Swedenborg, Joy Roy

  Acta biomaterialia.

  Collagen is the most abundant protein in mammals and provides the Abdominal Aortic Aneurysm (AAA) wall with mechanical strength, stiffness and toughness. Specifically, the spatial orientation ofCollagen is the most abundant protein in mammals and provides the Abdominal Aortic Aneurysm (AAA) wall with mechanical strength, stiffness and toughness. Specifically, the spatial orientation of collagen fibers in the wall has a major impact on its mechanical properties. Apart from valuable micro-histological information, this data can be integrated by histomechanical constitutive models thought to improve biomechanical simulations, i.e. to improve the biomechanical rupture risk assessment of AAAs. Tissue samples (n=24) from the AAA wall were harvested during elective AAA repair, fixated, embedded, sectioned and investigated under Polarized Light Microscopy. The birefringent properties of collagen were reinforced by picrosirius red staining and the three-dimensional collagen fiber orientations were identified with a universal rotary stage. Two constitutive models for collagen fibers were used to integrate the identified structural information in a macroscopic AAA wall model. The collagen fiber orientation in the AAA wall was considerably dispersed and could be captured by a Bingham distribution function (κ(1) = 11.6, κ(2) = 907). The dispersion was much larger in the tangential plane than in the cross-sectional plane and no significant difference amongst medial and adventitial layers could be identified. The layered directional organization of collagen in normal aortas was not evident in the AAA. The identified collagen organization combined with constitutive descriptions of collagen fibers that depend on its orientation, explain the anisotropic (orthotropic) mechanical properties of the AAA wall. The mechanical properties of collagen fibers largely depend on their undulation, which is an important structural parameter and requires further experimental investigation.

• Effect of strontium-substituted biphasic calcium-phosphate on inflammatory mediators production by human monocytes.

  Authors: E Buache, F Velard, E Bauden, C Guillaume, E Jallot, J M Nedelec, D Laurent-Maquin, P Laquerriere

  Acta biomaterialia.

  Calcium-phosphate materials are widely used as bone substitute because of their properties close to those of the mineral phase of bones. Nevertheless, after several months calcium-phosphate-basedCalcium-phosphate materials are widely used as bone substitute because of their properties close to those of the mineral phase of bones. Nevertheless, after several months calcium-phosphate-based materials release particles that may be phagocytised by monocytes, leading to an inflammatory reaction. Strontium is well known to counteract the osteoporosis process but little is known about its effect on inflammatory processes. The purpose of this work was to study the effect of biphasic calcium-phosphate (BCP) particles substituted with strontium on the inflammatory reaction. Human primary monocytes stimulated or not by lipopolysaccharide (LPS), were exposed to BCP particles containing strontium for 6 and 24 hours. Inflammatory mediators (cytokines and Matrix Metalloproteinases (MMPs)) production was then quantified by ELISA and zymography. We observed that the presence of strontium had few effects on unstimulated cells, but it decreased the production of pro-inflammatory cytokines and chemokine IL-8 in LPS-stimulated cells conditioned media. This work suggests for the first time that strontium may be involved in the control of inflammatory processes following BCP phagocytosis by human monocytes.

• Crystallization of bioinspired citrate-functionalized nanoapatite with tailored carbonate content.

  Authors: José Manuel Delgado-López, Michele Iafisco, Isaac Rodríguez, Anna Tampieri, María Prat, Jaime Gómez-Morales

  Acta biomaterialia.

  Novel citrate-functionalized carbonate-apatite nanoparticles with mean lengths ranging from 20 to 100 nm were synthesized by a thermal-decomplexing batch method. Needle-like and plate-shapedNovel citrate-functionalized carbonate-apatite nanoparticles with mean lengths ranging from 20 to 100 nm were synthesized by a thermal-decomplexing batch method. Needle-like and plate-shaped morphologies were obtained in the absence and in the presence of sodium carbonate in the precipitation medium, respectively. The precipitation time and the presence of sodium carbonate strongly affect the chemical composition as well as the dimensions and the crystallinity of nanoparticles. At short precipitation time, poorly crystalline 100 nm-mean length apatites with low carbonation degree (1.5% w/w, mainly in B-position) and high citrate content (5.9% w/w) were precipitated. This citrate content is close to that recently measured on bone apatite. When increasing the precipitation time up to 96 hours the mean length and the citrate content progressively decrease and at the same time the nanoparticles become more crystalline. They were composed of a well-ordered carbonate-substituted apatitic core embedded in a non-apatitic hydrated layer containing citrate ions. This layer progressively transforms into more stable apatite domain upon maturation in aqueous media. The nanoparticles displayed excellent compatibility properties in cell biology systems, since they were not cytotoxic to a mouse carcinoma cell line, when added until a final concentration of 100 μg mL-1. This work will provide new insights on the role of citrate in the crystallization of nanoapatites. Moreover, the synthesized nanoparticles are promising materials to be used as nano-carriers for local targeted drug delivery systems as well as building blocks for the preparation of nanostructured scaffolds for cells in bone tissue engineering.

• Actin cytoskeleton controls activation of Wnt/b-catenin signaling in mesenchymal cells on implant surfaces with different topography.

  Authors: C Galli, M Piemontese, S Lumetti, F Ravanetti, G M Macaluso, G Passeri

  Acta biomaterialia.

  Surface topography affects cell function and differentiation. It has been previously shown that rough surfaces can enhance the activation of canonical Wnt signaling, an important pathway forSurface topography affects cell function and differentiation. It has been previously shown that rough surfaces can enhance the activation of canonical Wnt signaling, an important pathway for osteoblast differentiation and bone maintenance, but the underlyinghe mechanisms are still poorly understood. The present paper investigates whether cytoskeletal organization contributes to regulating this pathway. Rho-associated protein kinase (ROCK), an important controller of actin microfilaments was inhibited with 2 mM specific antagonist Y-27632 in mesenchymal and osteoblastic cells growing on titanium discs with Polished or acid-etched, sand-blasted (SLA) surface. Y-27632 subverted the morphology of the cytoskeleton on Polished and, to a lesser extent, on SLA surfaces, as evidenced by fluorescence microscopy. Although ROCK inhibition did not affect cell viability, it increased activation of Wnt signaling in uncommitted C2C12 mesenchymal cells on Polished surfaces but not on SLA discs at reporter assay. Consistently with this, Real Time PCR analysis showed that MC3T3 cells on Polished surfaces expressed higher mRNA levels for b-catenin and Alkaline Phosphatase, a known Wnt target gene, and for the osteoblastic differentiation marker Osteocalcin after ROCK inhibition. Taken together, this data demonstrate that cytoskeletal organization mediates activation of Wnt canonical signaling in cells on titanium surfaces with different topography.

• Non-cross-linked porcine-based collagen I-III membranes do not require high vascularization rates for their integration within the implantation bed: a paradigm shift.

  Authors: Shahram Ghanaati

  Acta biomaterialia.

  There are conflicting reports concerning the tissue reaction of small animals to porcine-based, non-cross-linked collagen I-III membrane/matrices for use in guided tissue/bone regeneration. The fastThere are conflicting reports concerning the tissue reaction of small animals to porcine-based, non-cross-linked collagen I-III membrane/matrices for use in guided tissue/bone regeneration. The fast degradation of these membrane/matrices combined with transmembrane vascularization within four weeks has been observed in rats compared with the slow vascularization and continuous integration observed in mice. The aim of the present study was to analyze the tissue reaction to a porcine-based non-cross-linked collagen I-III membrane in mice. Using a subcutaneous implantation model, the membrane was implanted subcutaneously in mice for up to 60 days. The extent of scaffold vascularization, tissue integration and scaffold thickness were assessed using general and specialized histological methods together with a unique histomorphometrical analysis technique. A dense Bombyx mori-derived silk fibroin membrane was used as a positive control, whilst a poly-tetraflouroethylene (PTFE) membrane served as a negative control. Within the observation period, the collagen membrane induced a mononuclear cellular tissue response, including anti-inflammatory macrophages and the absence of multinucleated giant cells within its implantation bed. Transmembrane scaffold vascularization was not observed, whereas a mild scaffold vascularization was generated through micro-vessels located at both scaffold surfaces. However, the silk fibroin induced a mononuclear and multinucleated cell-based tissue response, in which pro-inflammatory macrophages and multinucleated giant cells were associated with an increasing transmembrane scaffold vascularization and a breakdown of the membrane within the experimental period. The PTFE membrane remained as a stable barrier throughout the study, and visible cellular degradation was not observed. However, multinucleated giant cells were located on both interfaces. The present study demonstrated that the tested non-cross-linked collagen membrane remained as a stable barrier membrane throughout the study period. The membrane integrated into the subcutaneous connective tissue and exhibited only a mild peripheral vascularization without experiencing breakdown. The silk fibroin, in contrast, induced granulation tissue formation, which resulted in its high vascularization and breakdown of the material over time. The presence of multinucleated giant cells at both interfaces of the PFTE membrane is a sign of its slow cellular biodegradation and might lead to adhesions between the membrane and its surrounding tissue. This hypothesis could explain the observed clinical complications associated with the retrieval of these materials after guided tissue regeneration.

• Multifunctional Particles for Melanoma-Targeted Drug Delivery.

  Authors: Aniket S Wadajkar, Zarna Bhavsar, Cheng-Yu Ko, Bhanuprasanth Koppolu, Weina Cui, Liping Tang, Kytai T Nguyen

  Acta biomaterialia.

  New magnetic-based core-shell particles (MBCSP) were developed to target skin cancer cells while delivering chemotherapeutic drugs in a controlled fashion. MBCSP consist of a thermo-responsive shellNew magnetic-based core-shell particles (MBCSP) were developed to target skin cancer cells while delivering chemotherapeutic drugs in a controlled fashion. MBCSP consist of a thermo-responsive shell of poly(N-isopropylacrylamide-acrylamide-allylamine) and a core of poly(lactic-co-glycolic acid) (PLGA) embedded with magnetite nanoparticles. To target melanoma cancer cells, MBCSP were conjugated with Gly-Arg-Gly-Asp-Ser (GRGDS) peptides that specifically bind to the α(5)β(3)(+) receptor of melanoma cell. MBCSP consist of unique multifunctional and controlled drug delivery characteristics. Specially, they can provide dual drug release mechanisms (a sustained release of drugs through degradation of PLGA core and a controlled release in response to changes in temperature via thermo-responsive polymer shell), and dual targeting mechanisms (magnetic localization and receptor-mediated targeting). Results from in vitro studies indicate that GRGDS-conjugated MBCSP has an average diameter of 296 nm and exhibit no cytotoxicity towards human dermal fibroblasts up to 500 μg ml(-1). Further, a sustained release of curcumin from the core and a temperature-dependent release of doxorubicin from the shell of MBCSP were observed. The particles also produced a dark contrast signal in magnetic resonance imaging. Finally, the particles were accumulated at the tumor site in a B16F10 melanoma orthotopic mouse model, especially in presence of a magnet. Results indicate great potential of MBCSP as a platform technology to target, treat, and monitor melanoma for targeted drug delivery to reduce side effects of chemotherapeutic reagents.

• Responsive Hydrogels Produced via Organic Sol-Gel Chemistry for Cell Culture Applications.

  Authors: Smruti Patil, Pulkit Chaudhury, Lisa Clarizia, Melisenda McDonald, Emmanuelle Reynaud, Peter Gaines, Daniel F Schmidt

  Acta biomaterialia.

  In this study, we report the synthesis of novel environmentally responsive polyurea hydrogel networks prepared via organic sol-gel chemistry and demonstrate that the networks can stabilize pH whileIn this study, we report the synthesis of novel environmentally responsive polyurea hydrogel networks prepared via organic sol-gel chemistry and demonstrate that the networks can stabilize pH while releasing glucose both in simple aqueous media and in mammalian cell culture settings. Hydrogel formulations have been developed based on the combination of an aliphatic triisocyanate with pH-insensitive amine functional polyether and pH-sensitive poly (ethyleneimine) segments in a minimally toxic solvent suitable for the sol-gel reaction. The polyether component of the polyurea network is sufficiently hydrophilic to give rise to some level of swelling independent of environmental pH, while the poly(ethyleneimine) component contains tertiary amine groups providing pH sensitivity to the network in the form of enhanced swelling and release under acidic conditions. The reaction of these materials to form a network is rapid and requires no catalyst. The resultant material exhibits the desired pH-responsive swelling behavior and demonstrates its ability to simultaneously neutralize lactic acid and release glucose in both cell-free culture media and mammalian cell culture, with no detectable evidence of cytotoxicity or changes in cell behavior, either in the case of SA-13 human hybridomas or mouse embryonic stem cells. Furthermore, pH is observed to have a clear effect on the rate at which glucose is released from the hydrogel network. Such characteristics promise to maintain a favorable cell culture environment in the absence of human intervention.

• Continuum modeling of neuronal cell under blast loading.

  Authors: Antoine Jérusalem, Ming Dao

  Acta biomaterialia.

  Traumatic brain injuries have recently been put under the spotlight as one of the most important causes of accidental brain dysfunctions. Significant experimental and modeling efforts are thusTraumatic brain injuries have recently been put under the spotlight as one of the most important causes of accidental brain dysfunctions. Significant experimental and modeling efforts are thus ongoing to study the associated biological, mechanical and physical mechanisms. In the field of cell mechanics, progresses are also being made at the experimental and modeling levels to better characterize many of the cell functions such as differentiation, growth, migration and death, among others. The work presented here aims at bridging both efforts by proposing a continuum model of neuronal cell submitted to blast loading. In this approach, cytoplasm, nucleus and membrane (plus cortex) are differentiated in a representative cell geometry, and different material constitutive models are adequately chosen for each one. The material parameters are calibrated against published experimental work of cell nanoidentation at multiple rates. The final cell model is ultimately subjected to blast loading within a complete fluid-structure interaction computational framework. The results are compared to the nanoindentation simulation and the specific effects of the blast wave on the pressure and shear levels at the interfaces are identified. As a conclusion, the presented model successfully captures some of the intrinsic intracellular phenomena occurring during its deformation under blast loading and potentially leading to cell damage. It suggests more particularly the localization of damage at the nucleus membrane similarly to what has already been observed at the overall cell membrane. This degree of damage is additionally predicted to be worsened by a longer blast positive phase duration. As a conclusion, the proposed model ultimately provides a new three dimensional computational tool to evaluate intracellular damage during blast loading.

• A novel furanone-modified antibacterial dental glass-ionomer cement.

  Authors: Yiming Weng, Leah Howard, Voon Joe Chong, Jun Sun, Richard L Gregory, Dong Xie

  Acta biomaterialia.

  A novel furanone derivative and its constructed polyacid were synthesized, characterized and formulated into the experimental high-strength cements. Compressive strength (CS) and S. mutans viabilityA novel furanone derivative and its constructed polyacid were synthesized, characterized and formulated into the experimental high-strength cements. Compressive strength (CS) and S. mutans viability were used to evaluate the mechanical strength and antibacterial activity of the cements. The effect of human saliva and aging were investigated. The effects of antibacterial activity on lactobacillus and of cytotoxicity on human pulp cells were also evaluated. The results show that all the formulated furanone-containing cements showed an antibacterial activity, accompanying with an initial CS reduction. The effect of the furanone derivative loading was significant. Increasing loading enhanced the antibacterial activity but reduced the initial CS of the formed cements. The derivative showed the antibacterial activity on both S. mutans and lactobacillus. The human saliva did not affect the antibacterial activity of the cement. The cytotoxicity study with human dental pulp cells shows that the furanone-modified cement was biocompatible. The 30-day aging study indicates that the cements may have a long-lasting antibacterial function. Within the limitations of this study, it appears that the experimental cement could be a clinically attractive dental restorative due to its high mechanical strength and antibacterial function.

• Polyethylene particles stimulate expression of ITAM-related molecules in peri-implant tissues and when stimulating osteoclastogenesis in vitro.

  Authors: E Alias, A S S K Dharmapatni, A C Holding, G J Atkins, D M Findlay, D W Howie, T N Crotti, D R Haynes

  Acta biomaterialia.

  Wear particle-induced orthopaedic prosthesis loosening is associated with elevated osteoclast activity. The immunoreceptor tyrosine-based activation motif (ITAM)-related molecules OSCAR, FcRγ, TREM2Wear particle-induced orthopaedic prosthesis loosening is associated with elevated osteoclast activity. The immunoreceptor tyrosine-based activation motif (ITAM)-related molecules OSCAR, FcRγ, TREM2 and DAP12 are important for osteoclast formation. The aim of this study was to determine if these molecules were involved with peri-implant loosening by investigating their expression in peri-implant tissues obtained at revision of joint replacement components containing polyethylene (PE) wear particles, and in osteoclasts formed in vitro in the presence of polyethylene particles. The results showed that there was a marked and statistically significant increase in protein levels of the ITAM-related molecules in the revision tissues. The levels of OSCAR, FcRγ, TREM2 and DAP12 mRNA in the revision tissues were also increased. In vitro, polyethylene particles stimulated osteoclast resorption in the presence of 50ng/ml of receptor activator NF kappa B (RANKL) and significantly elevated the expression of OSCAR, FcRγ, TREM2 and DAP12 during osteoclast formation. These findings suggest that the ITAM signalling molecules and their co-receptors have a role in pathogenic bone loss associated with implant polyethylene wear.

• Combination of media, biomaterials and extra cellular matrix proteins to enhance the differentiation of neural stem/precursor cells into neurons.

  Authors: Yi-Chen Li, Yong-Chong Lin, Tai-Horng Young

  Acta biomaterialia.

  The purpose of this study was to induce the differentiation of neural stem/precursor cells (NSPCs) more towards neurons than glial cells by the combination of media, biomaterials and extra cellularThe purpose of this study was to induce the differentiation of neural stem/precursor cells (NSPCs) more towards neurons than glial cells by the combination of media, biomaterials and extra cellular matrix (ECM) proteins. Considering the role of serum, 10% fetal bovine serum (FBS) or its fractions were added into DMEM/F12 medium to examine the effect of the differentiation-promoting potential on the cultured NSPCs, isolated from embryonic rat cerebral cortex. NSPCs were cultured for 7 days after which differentiation was assayed using immunocytochemistry for lineage specific markers. We demonstrated that neuron-differentiation promoting molecules were present in the serum with molecular weight less than 100 kDa, which could dominate the differentiation of NSPCs principally into neurons in the presence of basic fibroblast growth factor (bFGF). In contrast, NSPCs were induced to differentiate into glial cell phenotypes predominantly in the presence of whole serum components. Based on the serum fraction-containing medium, semi-quantification showed that the MAP2-positive percentage of immunoreactive ratio within migrated cells could be promoted over 85% by combining poly (ethylene-co-vinyl alcohol) (EVAL) biomaterial and fibronectin matrix protein. These results are very encouraging since a neuronal differentiation-favorable environment should be useful for the development of strategies for controlling the behaviors of NSPCs in neuroscience research.

• Influence of polyanion on physicochemical properties and biological activities of polyanion/DNA/polycation ternary polyplex.

  Authors: Cuifeng Wang, Xin Luo, Yuefang Zhao, Lina Han, Xin Zeng, Min Feng, Shirong Pan, Hui Peng, Chuanbin Wu

  Acta biomaterialia.

  It was recently reported that polyanion/DNA/polycation ternary polyplex markedly improved gene transfection activity in comparison to the original DNA/polycation binary polyplex. In this study, toIt was recently reported that polyanion/DNA/polycation ternary polyplex markedly improved gene transfection activity in comparison to the original DNA/polycation binary polyplex. In this study, to explore the influence of polyanion on physicochemical properties and biological activities of polyanion/pDNA/polycation ternary polyplex, four types of biocompatible polyanions were selected mainly based on their acid strengths of anionic function groups and molecular rigidity to form ternary polyplexes with PEI 25 kDa and DNA. That polyanions loosened DNA polyplex, weakened adsorption of serum proteins and improved cellular uptake, which are thought of as the important factors leading to the high transfection efficiency of DNA ternary polyplex, were specifically investigated. Electrophoresis retardation analysis indicated that the loosening capacities of polyanions depended on the pKa values of the functional anion groups as well as the flexibility of polyanions. The low pKa and flexible structure of polyanions tended to easily loosen the compact DNA polyplex. The thermodynamic analysis with isothermal titration calorimetry provided the direct evidences about the serum proteins and DNA ternary polyplex interactions. The polyanion/pDNA/polycation ternary polyplex exhibited obviously lower binding affinities and less adsorption to serum protein, compared with the original DNA/polycation binary polyplex. These relatively stable DNA ternary polyplexes in serum containing medium maintained the high levels of cellular uptake and intracellular accumulation that was correlated with their high transfection efficiency. In contrast, their original pDNA/polycation binary polyplex formed clustered polyplex by strong adsorption of large amounts of serum proteins, leading to the sharp reduction of cellular uptake and intracellular accumulation, and then low gene transfer efficiency. These results provided a basis of the development of polyanion/DNA/polycation ternary polyplex for polyfection.

• Novel silk fibroin/elastin wound dressings.

  Authors: Andreia Vasconcelos, Andreia C Gomes, Artur Cavaco-Paulo

  Acta biomaterialia.

  Silk fibroin (SF) and elastin (EL) scaffolds were successfully produced for the first time for the treatment of burn wounds. The self-assembly properties of SF, together with the excellent chemicalSilk fibroin (SF) and elastin (EL) scaffolds were successfully produced for the first time for the treatment of burn wounds. The self-assembly properties of SF, together with the excellent chemical and mechanical stability and, biocompatibility, were combined with elastin protein to produce scaffolds with the ability to mimic the extracellular matrix (ECM). Porous scaffolds were obtained by lyophilization and were further crosslinked with genipin (GE). Genipin crosslinking induces the conformational transition from random coil to β-sheet of SF chains yielding scaffolds with smaller pore size, reduced swelling ratios, degradation and release rates. All results indicated that the composition of the scaffolds had a significant effect on their physical properties, and that can easily be tuned to obtain scaffolds suitable for biological applications. Wound healing was assessed through the use of human full-thickness skin equivalents (EpidermFT). Standardized burn wounds were induced by a cautery and the best re-epithelialization and the fastest wound closure was obtained in wound treated with 50SF scaffold that contain the highest amount of elastin after 6 days of healing in comparison with other dressings and controls. The cytocompatibility demonstrated with human skin fibroblasts together with the healing improvement make these SF/EL scaffolds suitable for wound dressing applications.

• High Mesenchymal Stem Cell Seeding Densities in Hyaluronic Acid Hydrogels Produce Engineered Cartilage with Native Tissue Properties.

  Authors: Isaac E Erickson, Sydney R Kestle, Kilief H Zellars, Megan J Farrell, Minwook Kim, Jason A Burdick, Robert L Mauck

  Acta biomaterialia.

  Engineered cartilage based on adult mesenchymal stem cells (MSCs) is an alluring goal for the repair of articular defects. However, efforts to date have failed to generate constructs with sufficientEngineered cartilage based on adult mesenchymal stem cells (MSCs) is an alluring goal for the repair of articular defects. However, efforts to date have failed to generate constructs with sufficient mechanical properties to function in the demanding environment of the joint. Our findings with a novel photocrosslinked hyaluronic acid (HA) hydrogel suggest that stiff gels (high HA concentration, 5% w/vol) foster chondrogenic differentiation and matrix production, but limit overall functional maturation due to the inability of formed matrix to diffuse away from the point of production and form a contiguous network. In the current study, we hypothesized that increasing the MSC seeding density would decrease the required diffusional distance, and so expedite the development of functional properties. To test this hypothesis, bovine MSCs were encapsulated at seeding densities of either 20 or 60 million cells per mL in 1%, 3%, and 5% (w/vol) hyaluronic acid (HA) hydrogels. Counter our hypothesis, higher concentration HA gels (3% and 5%) did not develop more rapidly with increased MSC seeding density. However, the biomechanical properties of low concentration (1%) HA constructs increased markedly (nearly 3-fold with a 3-fold increase in seeding density). To ensure that optimal nutrient access was delivered, we next cultured these constructs under dynamic culture conditions (orbital shaking) for 9 weeks. Under these conditions, 1% HA seeded at 60 million MSCs per mL reached a compressive modulus in excess of 1 MPa (compared to 0.3-0.4MPa for free swelling constructs). This is the highest level we have reported to date in this HA hydrogel system, and represents a significant advance towards functional stem cell-based tissue engineered cartilage.

• Orthopaedic applications of silicon nitride ceramics.

  Authors: B Sonny Bal, Mohamed N Rahaman

  Acta biomaterialia.

  Silicon nitride (Si(3)N(4)) is a ceramic material that was developed for industrial applications that demand high strength and fracture resistance under extreme operating conditions. Recently,Silicon nitride (Si(3)N(4)) is a ceramic material that was developed for industrial applications that demand high strength and fracture resistance under extreme operating conditions. Recently, Si(3)N(4) has been used as an orthopaedic biomaterial, to promote bone fusion in spinal surgery, and to develop bearings that can improve the wear and longevity of prosthetic hip and knee joints. Si(3)N(4) has been implanted in human patients for over three years now, and clinical trials with Si(3)N(4) femoral heads in prosthetic hip replacement are contemplated. This review will provide background information and data related to Si(3)N(4) ceramics that will be of interest to engineering and medical professionals.

• A review of the application of anodization for the fabrication of nanotubes on metal implant surfaces.

  Authors: Sepideh Minagar, Christopher C Berndt, James Wang, Elena Ivanova, Cuie Wen

  Acta biomaterialia.

  Metal implants are the best choice for the long-term replacement of hard tissue, such as hip and knee joints, because of their excellent mechanical properties. Titanium and its alloys, due to theirMetal implants are the best choice for the long-term replacement of hard tissue, such as hip and knee joints, because of their excellent mechanical properties. Titanium and its alloys, due to their self-organized oxide layer that protects the surface from corrosion and prevents ion release, are widely accepted as biocompatible metal implants. Surface modification is essential for the promotion of the osseointegration of these biomaterials. Nanotubes fabricated on the surface of metal implants by anodization are receiving ever-increasing attention for surface modification. This paper provides an overview of the employment of anodization for nanotubes fabricated on the surface of titanium, titanium alloys and titanium alloying metals such as niobium, tantalum and zirconium metal implants. This work explains anodic oxidation and the manner by which nanotubes form on the surface of the metals. It then assesses this topical research to indicate how changes in anodizing conditions influence nanotube characteristics such as tube diameters and nanotube-layer thickness.

• Performance of electrospun poly(ε-caprolactone) fiber meshes used with mineral trioxide aggregates in the pulp capping procedure.

  Authors: Woocheol Lee, Joung-Hwan Oh, Joo-Cheol Park, Hong-In Shin, Jeong-Hwa Baek, Hyun-Mo Ryoo, Kyung Mi Woo

  Acta biomaterialia.

  Living dental pulp tissue exposed to the oral environment should be protected with an appropriate pulp capping material to support the dentinogenesis potential of the pulp cells. Mineral trioxideLiving dental pulp tissue exposed to the oral environment should be protected with an appropriate pulp capping material to support the dentinogenesis potential of the pulp cells. Mineral trioxide aggregate (MTA) is the material of choice for the treatment of pulp. However, due to cytotoxicity during the initial setting phase of MTA, a new material is required that can act as a barrier to direct contact but facilitate the favorable effect of MTA. This study examined the feasibility of using electrospun poly(ε-caprolactone) fiber (PCL-F) meshes in the MTA-based pulp capping procedures. An experimental pulp capping was performed on the premolars of beagle dogs, and the efficacy of the PCL-F meshes was evaluated after 8 weeks. PCL-F/MTA formed dentin bridge that was approximately 4-fold thicker than that formed by the MTA. Columnar polarized odontoblast-like cells with long processes and tubular dentin-like matrices were observed beneath the dentin bridge in the PCL-F/MTA. The cells were also intensely immuno-stained for dentin sialoprotein. In cell cultures, PCL-F/MTA reduced cell death to approximately 8% of that in the MTA group. The proliferation of the cells cultured on PCL-F/MTA was much greater than that of cells cultured on MTA. Furthermore, PCL-F/MTA promoted the differentiation of MDPC23 cells to odontoblast-like cells and biomineralization, as confirmed by the expression of alkaline phosphatase and dentin sialophosphoprotein and by the deposition of calcium. Based on these histologic findings and the cell responses observed in this study, PCL-F may be used efficiently in the MTA-based dental pulp therapy.

• Folate-PEG-superparamagnetic iron oxide nanoparticles for lung cancer imaging.

  Authors: Mi-Kyong Yoo, In-Kyu Park, Hwang-Tae Lim, Sang-Joon Lee, Hu-Lin Jiang, You-Kyoung Kim, Yun-Jaie Choi, Myung-Haing Cho, Chong-Su Cho

  Acta biomaterialia.

  While superparamagnetic iron oxide nanoparticles (SPIONs) have been widely used in biomedical applications, rapid blood clearance, instability and active targeting of the SPIONs limit theirWhile superparamagnetic iron oxide nanoparticles (SPIONs) have been widely used in biomedical applications, rapid blood clearance, instability and active targeting of the SPIONs limit their availability for clinical trials. This work aimed to develop stable and lung cancer targeted SPIONs. For this purpose, firstly the folic acid (FA)-conjugated poly(ethylene glycol)(FA-PEG) was synthesized and FA-PEG-SPIONs were subsequently prepared by reaction of FA-PEG and aminosilane-immobilized SPIONs. Cy 5.5 was labeled with the FA-PEG-SPIONs for optical imaging. The intracellular uptake of the FA-PEG-SPIONs-Cy 5.5 was evaluated in KB cells and lung cancer mice to confirm the active targeting. Sizes of the FA-PEG-SPIONs were not much changed up to 8 weeks at 4 °C, suggestive of very stable particle sizes. From results of fluorescent flow cytometry and confocal laser scanning microscopy, intracellular uptake of FA-PEG-SPIONs-Cy 5.5 was highly inhibited by pre-treatment of free folic acid, indication of receptor-mediated endocytosis. Stronger optical imaging was observed in the lung cancer mice by FA-PEG-SPIONs-Cy 5.5 after 6 and 24 h post-injection through tail vein than PEG-SPIONs-Cy 5.5 due to the receptor-mediated endocytosis.

• Comparative study on osteogenic potential of a composite scaffold incorporating either endogenous bone morphogenetic protein-2 or exogenous phytomolecule icaritin - an in vitro efficacy study.

  Authors: Shi-Hui Chen, Xin-Luan Wang, Xin-Hui Xie, Li-Zhen Zheng, Dong Yao, Da-Ping Wang, Yang Leng, Ge Zhang, Ling Qin

  Acta biomaterialia.

  Local delivery system with sustained and efficient release of therapeutic agents from an appropriate carrier is desirable for orthopedic applications. We fabricated novel composite scaffolds made ofLocal delivery system with sustained and efficient release of therapeutic agents from an appropriate carrier is desirable for orthopedic applications. We fabricated novel composite scaffolds made of poly (lactic-co-glycolic acid) with tricalcium phosphate (PLGA/TCP) by an advanced low-temperature rapid prototyping technique that were incorporated with either endogenous bone morphogenetic protein-2 (BMP-2) (PLGA/TCP/BMP-2) or phytomolecule icaritin (PLGA/TCP/icaritin) at low, middle and high doses. PLGA/TCP served as control. In vitro degradation, osteogenesis and release tests showed statistical difference among PLGA/TCP/icaritin, PLGA/TCP and PLGA/TCP/BMP-2 groups, where PLGA/TCP/icaritin had desired slow release of bioactive icaritin in a dose-dependent manner while there was almost no BMP-2 release from the PLGA/TCP/BMP-2 scaffolds. PLGA/TCP/icaritin significantly increased more ALP activity, up-regulated mRNA expression of osteogenic genes and enhanced calcium deposition and mineralization in rabbit BMSCs cultured on scaffolds as compared with other two groups. These results indicated a desired degradation rate, osteogenic capability and release property in PLGA/TCP/icaritin composite scaffold as icaritin preserved its bioactivity and structure after its incorporation, while PLGA/TCP/BMP-2 did not show an initially expected osteogenic potential due to loss of the original bioactivity of BMP-2 during its incorporating and fabrication procedure. Our results suggested that PLGA/TCP composite scaffolds incorporating osteogenic icaritin might be a promising approach for bone tissue bioengineering and regeneration.

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