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Tissue engineering (TE) envisions the creation of functional substitutes for damaged tissues through integrated solutions, where medical, biological, and engineering principles are combined. Bone regeneration is one of the areas in which designing a model that mimics all tissue properties is still a challenge. The hierarchical structure and high vascularization of bone hampers a TE approach, especially in large bone defects. Nanotechnology can open up a new era for TE, allowing the creation of nanostructures that are comparable in size to those appearing in natural bone. Therefore, nanoengineered systems are now able to more closely mimic the structures observed in naturally occurring systems, and it is also possible to combine several approaches - such as drug delivery and cell labeling - within a single system. This review aims to cover the most recent developments on the use of different nanoparticles for bone TE, with emphasis on their application for scaffolds improvement; drug and gene delivery carriers, and labeling techniques. ; This study was funded by QREN (ON.2 - NORTE-01-0124-FEDER-000018), as well as the European Union's FP7 Programme under grant agreement number REGPOTCT2012-316331-POLARIS. Sılvia Vieira was awarded an FCT PhD scholarship (SFRH/BD/102710/2014). The FCT distinction attributed to J.M.O. under the Investigator FCT program (IF/00423/2012 and IF/01285/2015) is also greatly acknowledged. ...

Multiscale analysis has become an attractive technique to predict the behaviour of materials whose microstructure strongly changes spatially or among samples, with that microstructure controlling the local constitutive behaviour. This is the case, for example, of most biological tissues—such as bone. Multiscale approaches not only allow, not only to better characterise the local behaviour, but also to predict the field-variable distributions (e.g., strains, stresses) at both scales (macro and micro) simultaneously. However, multiscale analysis usually lacks su cient experimental feedback to demonstrate its validity. In this paper an experimental and numerical micromechanics analysis is developed with application to cortical bone. Displacement and strain fields are obtained across the microstructure by means of digital image correlation (DIC). The other mechanical variables are computed following the micromechanics theory. Special emphasis is given to the di erences found in the di erent field variables between the micro- and macro-structures, which points out the need for this multiscale approach in cortical bone tissue. The obtained results are used to establish the basis of a multiscale methodology with application to the analysis of bone tissue mechanics at di erent spatial scales. ; The authors gratefully acknowledge the Ministry of Economy and Competitiveness [Ministerio de Economia y Competitividad] of the Government of Spain (DPI2014-58233-P, DPI2017-82501-P, PGC2018-097257-B-C31) for research funding.

Three novel borosilicate bioactive glasses (BBGs) were prepared and used to investigate their bioactive and antibacterial properties. The BBGs were prepared by melt quenching using different glass modifiers, i.e. Mg2+, Ca2+ and Sr2+, and their amorphous nature was confirmed by X-ray diffraction. Scanning electron microscopy with energy dispersive X-ray spectroscopy allowed the visualization of apatite-like structures upon 7 days of immersion in simulated body fluid. BBG-Ca generated surface structures with a Ca/P ratio â 1.67, while the surface of the BBG-Sr was populated with structures with a Sr/P ratio â 1.7. Moreover, bacterial tests showed that the BBG-Mg and BBG-Sr glasses (at concentrations of 9, 18, 36 and 72 mg/mL) present antibacterial characteristics. In particular, BBG-Sr, at concentrations of 9 mg/mL, exhibited bacteriostatic activity against Pseudomonas aeruginosa, and at concentrations â ¥ 18 mg/mL it was able to eradicate this bacterium. These results evidence an antibacterial activity dependent on the BBGs composition, concentration and bacterial species. Cellular studies showed that the developed BBGs do not present statistically significant cytotoxic effect against Saos-2 cells after 3 days of culture showing better performance (in the cases of BBG-Ca and BBG-Sr) than commercial 45S5 Bioglass up to 7 days of culture. Overall, this study demonstrates that BBGs can be effectively designed to combine bioactivity and intrinsic antibacterial activity targeting bone tissue engineering applications. ; The authors gratefully acknowledge financial support from Portuguese Foundation for Science and Technology (Ph.D. grant BD/73162/2010 to JSF); European Union's Seventh Framework Programme (FP7/2007−2013) under Grant No. REGPOT-CT2012-31633-POLARIS to RAP and MM; and QREN project (RL3 − TEC1 − NORTE-01-0124-FEDER000020) cofinanced by North Portugal Regional Operational Programme (ON.2 − O Novo Norte), under the NSRF, through the ERDF (to MM); and the European Research Council under grant agreement ...

Bioceramic scaffolds are crucial in tissue engineering for bone regeneration. They usually provide hierarchical porosity, bioactivity, and mechanical support supplying osteoconductive properties and allowing for 3D cell culture. In the case of age-related diseases such as osteoarthritis and osteoporosis, or other bone alterations as alveolar bone resorption or spinal fractures, functional tissue recovery usually requires the use of grafts. These bone grafts or bone void fillers are usually based on porous calcium phosphate grains which, once disposed into the bone defect, act as scaffolds by incorporating, to their own porosity, the intergranular one. Despite their routine use in traumatology and dental applications, specific graft requirements such as osteoinductivity or balanced dissolution rate are still not completely fulfilled. Marine origin bioceramics research opens the possibility to find new sources of bone grafts given the wide diversity of marine materials still largely unexplored. The interest in this field has also been urged by the limitations of synthetic or mammalian-derived grafts already in use and broadly investigated. The present review covers the current stage of major marine origin bioceramic grafts for bone tissue regeneration and their promising properties. Both products already available on the market and those in preclinical phases are included. To understand their clear contribution to the field, the main clinical requirements and the current available biological-derived ceramic grafts with their advantages and limitations have been collected. ; This research was partially supported by the European Union projects 0245_IBEROS_1_E and 0302_CVMAR_I_1_P, both from Interreg V-A Spain-Portugal (POCTEP 2015) and BLUEHUMAN EAPA_151/2016 from INTERREG Atlantic Area, European Regional Development Fund. Moreover, regional funds from Competitive Reference Groups (GRC) ED431C 2016/008 and ED431C 2017_51 and Research networks ED431D 2017/13 both from Xunta de Galicia (Spain) are also acknowledged. ...

Accepted manuscript ; The preparation of three-dimensional polycaprolactone scaffolds using dense CO2 as foaming agent, without supercritical conditions, was evaluated in this study towards future applications in bone repair. Herein, 3D foams were obtained at 5.0 MPa and 45 °C. To induce bioactivity, β-tricalcium phosphate (β-TCP, 10 wt%) and dexamethasone (5 and 10 wt%) were dispersed in the scaffolds. Foams revealed a pore size range of 164–882 μm, 73–99% porosity and 79–99% interconnectivity, assessed by micro-computed tomography, and a Young modulus of 1.76–2.92 MPa. Dexamethasone did not impair morphology of the matrices in comparison with PCL+β-TCP, which presented a water uptake of nearly 100% after 14 days. A sustained release of dexamethasone was achieved over 35 days in physiologic solution. This study reports the feasibility of using dense CO2 to produce in one-step a porous matrix loaded with active agents opening new possibilities towards injectable systems for in situ foaming ; European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement number REGPOT-CT2012-316331-POLARIS. It was also funded by the project "Novel smart and biomimetic materials for innovative regenerative medicine approaches" (RL1-ABMR-NORTE-01-0124-FEDER-000016) co-financed by North Portugal Regional Operational Programme (ON.2 – O Novo Norte), under the National Strategic Reference Framework (NSRF), through the European Regional Development Fund (ERDF) and the project NORTE‐01‐0145‐FEDER‐000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement. The authors would like to acknowledge the funding of the project Associate Laboratory ICVS/3B's, under grant agreement number POCI-01-0145-FEDER-007038 supported by FEDER, through the Competitiveness Factors Operational Programme (COMPETE), and by National funds, through the Foundation for Science and Technology (FCT) ...

Tissue engineering and regenerative medicine has been providing exciting technologies for the development of functional substitutes aimed to repair and regenerate damaged tissues and organs. Inspired by the hierarchical nature of bone, nanostructured biomaterials are gaining a singular attention for tissue engineering, owing their ability to promote cell adhesion and proliferation, and hence new bone growth, compared with conventional microsized materials. Of particular interest are nanocomposites involving biopolymeric matrices and bioactive nanosized fi llers. Biodegradability, high mechanical strength, and osteointegration and formation of ligamentous tissue are properties required for such materials. Biopolymers are advantageous due to their similarities with extracellular matrices, specifi c degradation rates, and good biological performance. By its turn, calcium phosphates possess favorable osteoconductivity, resorbability, and biocompatibility. Herein, an overview on the available natural polymer/calcium phosphate nanocomposite materials, their design, and properties is presented. Scaffolds, hydrogels, and fi bers as biomimetic strategies for tissue engineering, and processing methodologies are described. The specifi c biological properties of the nanocomposites, as well as their interaction with cells, including the use of bioactive molecules, are highlighted. Nanocomposites in vivo studies using animal models are also reviewed and discussed. ; The research leading to this work has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement no REGPOT-CT2012-316331-POLARIS, and from QREN (ON.2 - NORTE-01-0124-FEDER-000016) cofinanced by North Portugal Regional Operational Program (ON.2 - O Novo Norte), under the National Strategic Reference Framework (NSRF), through the European Regional Development Fund ...

The lack of a functional vascular supply has, to a large extent, hampered the whole range of clinical applications of 'successful' laboratory-based bone tissue engineering strategies. To the present, grafts have been dependent on post-implant vascularization, which jeopardizes graft integration and often leads to its failure. For this reason, the development of strategies that could effectively induce the establishment of a microcirculation in the engineered constructs has become a major goal for the tissue engineering research community. This review addresses the role and importance of the development of a vascular network in bone tissue engineering and provides an overview of the most up to date research efforts to develop such a network. ; M. I. Santos would like to acknowledge the Portuguese Foundation for Science and Technology (FCT) for her Ph.D. grant (SFRH/BD/13428/2003). This work was partially supported by FCT through funds from POCTI and/or FEDER programs and by the European Union funded STREP Project HIPPOCRATES (NMP3-CT-2003-505758). This work was carried out under the scope of the European NoE EXPERTISSUES (NMP3-CT-2004-500283). The authors also acknowledge Gabriela A. Silva for critically reading the ...

The creation of man-made living implants is the holy grail of tissue engineering (TE). As basic science advances, one of the major challenges in TE is the translation of the increasing biological knowledge on complex cell and tissue behavior into a predictive and robust engineering process. Mastering this complexity is an essential step towards clinical applications of TE. Computational modeling allows to study the biological complexity in a more integrative and quantitative way. Specifically, computational tools can help in quantifying and optimizing the TE product and process but also in assessing the influence of the in vivo environment on the behavior of the TE product after implantation. In this talk, I will use the example of bone tissue engineering to demonstrate how computational modeling can contribute in all aspects of the TE product development cycle: cells, carriers, culture conditions and clinics (figure 1 and 2). Depending on the specific question that needs to be answered the optimal model systems can vary from single scale to multiscale. Furthermore, depending on the available information, model systems can be purely data-driven or more hypothesis-driven in nature. The talk makes the case for in silico models receiving proper recognition, besides the in vitro and in vivo work in the TE field. Figure 1: overview of the 4 important components in bone tissue engineering: cells, carriers, culture and clinics. Figure 2: overview of in silico contributions to the 4 important components in bone tissue engineering: cells [1], carriers, culture [3] and clinics [4]. Acknowledgements This work presented in this talk is part of Prometheus, the KU Leuven R&D division for skeletal tissue engineering. http://www.kuleuven.be/prometheus. The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013) / ERC Grant Agreements 279100; from the Research Programme of the Research Foundation - Flanders (FWO, grant n. G.0982.11), from the Belgian National Fund for Scientific Research (FNRS) and from the special research fund of the KU Leuven (GOA/13/016) References 1. Kerkhofs J, Roberts SJ, Luyten FP, Van Oosterwyck H, Geris L. Relating the chondrocyte gene network to growth plate morphology: from genes to phenotype. PLoS One. 2012;7(4):e34729. doi:10.1371/journal.pone.0034729 2. Guyot Y, Papantoniou I, Chai YC, Van Bael S, Schrooten J, Geris L. A computational model for cell/ECM growth on 3D surfaces using the level set method: a bone tissue engineering case study.Biomech Model Mechanobiol. 2014 3. Carlier A, Geris L, Bentley K, Carmeliet G, Carmeliet P, Van Oosterwyck H. MOSAIC: a multiscale model of osteogenesis and sprouting angiogenesis with lateral inhibition of endothelial cells. PLoS Comput Biol. 2012;8(10):e1002724. ; Peer reviewed