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Publications

by Keyword: Mineralization

Alambiaga-Caravaca, Adrian M, Chou, Yu Fu, Moreno, Daniel, Aparicio, Conrado, Lopez-Castellano, Alicia, Feitosa, Victor Pinheiro, Tezvergil-Mutluay, Arzu, Sauro, Salvatore, (2024). Characterisation of experimental flowable composites containing fluoride-doped calcium phosphates as promising remineralising materials Journal Of Dentistry 143, 104906

Objective: Remineralising composites with antibacterial properties may seal the cavity and prevent secondary caries. This study aimed at developing experimental flowable composites containing different concentrations of fluoride-doped calcium phosphate fillers and evaluating their remineralising and antibacterial properties. Methods: Experimental resin-based composites containing different concentrations (0-20 %) of fluoride-doped calcium phosphate fillers (VS10/VS20) were formulated. The release of calcium (Ca), phosphate (PO) and fluoride (F) ions was assessed for 30 days. Remineralisation properties were evaluated through ATR-FTIR and SEM/EDX after storage in simulated body fluid (SBF). The metabolic activity and viability of Streptococcus gordonii was also evaluated through ATP, CFU and live/dead confocal microscopy. The evaluation of specific monomer elution from the experimental composites was conducted using high-performance liquid chromatography (HPLC). Results: The composites containing VS10 showed the highest release of Ca, those containing VS20 released more F over time (p < 0.05), while there was no significant difference in terms of PO ions release between the groups (p > 0.05). A quick 7-day mineral precipitation was observed in the tested composites containing VS10 or VS20 at 10 %; these materials also showed the greatest antibacterial activity (p < 0.05). Moreover, the tested composites containing VS10 presented the lowest elution of monomers (p < 0.05). Conclusions: Innovative composites were developed with low monomers elution, evident antibacterial activity against S. gordonii and important remineralisation properties due to specific ions release.

JTD Keywords: Antibacterial, Apatite, Apatite, bacterial, caries, demineralization, dentistry, monomers, adhesion, elution, enamel, tissu, Calcium phosphate, Ion-release, Remineralisation, Remineralisation, ion -release, antibacterial, calcium phosphate, resin composite, apatit, Resin composite


Ye, Z, Qi, YP, Zhang, AQ, Karels, BJ, Aparicio, C, (2023). Biomimetic Mineralization of Fibrillar Collagen with Strontium-doped Hydroxyapatite Acs Macro Letters 12, 408-414

Fibrillar collagen structures mineralized with hydroxyapatite using the polymer-induced liquid precursor (PILP) process have been explored as synthetic models for studying biomineralization of human hard tissues and have also been applied in the fabrication of scaffolds for hard tissue regeneration. Strontium has important biological functions in bone and has been used as a therapeutic agent for treating diseases that result in bone defects, such as osteoporosis. Here, we developed a strategy to mineralize collagen with Sr-doped hydroxyapatite (HA) using the PILP process. Doping with Sr altered the crystal lattice of HA and inhibited the degree of mineralization in a concentration-dependent manner, but did not affect the unique formation of intrafibrillar minerals using the PILP. The Sr-doped HA nanocrystals were aligned in the [001] direction but did not recapitulate the parallel alignment of the c-axis of pure Ca HA in relation to the collagen fiber long axis. The mimicry of doping Sr in PILP-mineralized collagen can help understand the doping of Sr in natural hard tissues and during treatment. The fibrillary mineralized collagen with Sr-doped HA will be explored in future work as biomimetic and bioactive scaffolds for regeneration of bone and tooth dentin.

JTD Keywords: bone regeneration, osteoblast differentiation, osteoporosis, ranelate, risk, scaffolds, women, Intrafibrillar mineralization


Mochi, F, Scatena, E, Rodriguez, D, Ginebra, MP, Del Gaudio, C, (2022). Scaffold-based bone tissue engineering in microgravity: potential, concerns and implications Npj Microgravity 8, 45

One of humanity's greatest challenges is space exploration, which requires an in-depth analysis of the data continuously collected as a necessary input to fill technological gaps and move forward in several research sectors. Focusing on space crew healthcare, a critical issue to be addressed is tissue regeneration in extreme conditions. In general, it represents one of the hottest and most compelling goals of the scientific community and the development of suitable therapeutic strategies for the space environment is an urgent need for the safe planning of future long-term manned space missions. Osteopenia is a commonly diagnosed disease in astronauts due to the physiological adaptation to altered gravity conditions. In order to find specific solutions to bone damage in a reduced gravity environment, bone tissue engineering is gaining a growing interest. With the aim to critically investigate this topic, the here presented review reports and discusses bone tissue engineering scenarios in microgravity, from scaffolding to bioreactors. The literature analysis allowed to underline several key points, such as the need for (i) biomimetic composite scaffolds to better mimic the natural microarchitecture of bone tissue, (ii) uniform simulated microgravity levels for standardized experimental protocols to expose biological materials to the same testing conditions, and (iii) improved access to real microgravity for scientific research projects, supported by the so-called democratization of space.© 2022. The Author(s).

JTD Keywords: biomaterials, collagen/hydroxyapatite, composite scaffolds, in-vitro, mineralization, proliferation, regenerative medicine, stem-cells, vivo, Hydroxyapatite scaffolds


Bonany, M, del-Mazo-Barbara, L, Espanol, M, Ginebra, MP, (2022). Microsphere incorporation as a strategy to tune the biological performance of bioinks Journal Of Tissue Engineering 13, 20417314221119896

Although alginate is widely used as a matrix in the formulation of cell-laden inks, this polymer often requires laborious processing strategies due to its lack of cell adhesion moieties. The main objective of the present work was to explore the incorporation of microspheres into alginate-based bioinks as a simple and tuneable way to solve the cell adhesion problems, while adding extra biological functionality and improving their mechanical properties. To this end, three types of microspheres with different mineral contents (i.e. gelatine with 0% of hydroxyapatite, gelatine with 25 wt% of hydroxyapatite nanoparticles and 100 wt% of calcium -deficient hydroxyapatite) were synthesised and incorporated into the formulation of cell-laden inks. The results showed that the addition of microspheres generally improved the rheological properties of the ink, favoured cell proliferation and positively affected osteogenic cell differentiation. Furthermore, this differentiation was found to be influenced by the type of microsphere and the ability of the cells to migrate towards them, which was highly dependent on the stiffness of the bioink. In this regard, Ca2+ supplementation in the cell culture medium had a pronounced effect on the relaxation of the stiffness of these cell-loaded inks, influencing the overall cell performance. In conclusion, we have developed a powerful and tuneable strategy for the fabrication of alginate-based bioinks with enhanced biological characteristics by incorporating microspheres into the initial ink formulation.; [GRAPHICS]; .

JTD Keywords: 3d bioprinting, alginate, bioink, gelatine, hydroxyapatite, 3d bioprinting, Alginate, Behavior, Bioink, Cell-culture, Gelatin, Gelatine, Hydrogels, Hydroxyapatite, Laden, Microspheres, Mineralization, Scaffolds


Khurana, K., Guillem-Marti, J., Soldera, F., Mücklich, F., Canal, C., Ginebra, M. P., (2020). Injectable calcium phosphate foams for the delivery of Pitavastatin as osteogenic and angiogenic agent Journal of Biomedical Materials Research - Part B Applied Biomaterials 108, (3), 760-770

Apatitic bone cements have been used as a clinical bone substitutes and drug delivery vehicles for therapeutic agents in orthopedic applications. This has led to their combination with different drugs with known ability to foster bone formation. Recent studies have evaluated Simvastatin for its role in enhanced bone regeneration, but its lipophilicity hampers incorporation and release to and from the bone graft. In this study, injectable calcium phosphate foams (i-CPF) based on α-tricalcium phosphate were loaded for the first time with Pitavastatin. The stability of the drug in different conditions relevant to this study, the effect of the drug on the i-CPFs properties, the release profile, and the in vitro biological performance with regard to mineralization and vascularization were investigated. Pitavastatin did not cause any changes in neither the micro nor the macro structure of the i-CPFs, which retained their biomimetic features. PITA-loaded i-CPFs showed a dose-dependent drug release, with early stage release kinetics clearly affected by the evolving microstructure due to the setting of cement. in vitro studies showed dose-dependent enhancement of mineralization and vascularization. Our findings contribute towards the design of controlled release with low drug dosing bone grafts: i-CPFs loaded with PITA as osteogenic and angiogenic agent.

JTD Keywords: Controlled drug release, Endothelial progenitor cells, Mineralization, Rat mesenchymal stem cells, Vascularization


Fernández-Remolar, D. C., Santamaría, J., Amils, R., Parro, V., Gómez-Ortíz, D., Izawa, M. R. M., Banerjee, N. R., Pérez-Rodríguez', R., Rodríguez, N., López-Martínez, N., (2015). Formation of iron-rich shelled structures by microbial communities Journal of Geophysical Research: Biogeosciences , 120, (1), 147-168

In this paper, we describe the discovery and characterization of shelled structures that occur inside galleries of Pyrenees mines. The structures are formed by the mineralization of iron and zinc oxides, dominantly franklinite (ZnFe2O4) and poorly ordered goethite (α-FeO(OH)). Subsurface oxidation and hydration of polymetallic sulfide orebodies produce solutions rich in dissolved metal cations including Fe2+/3+ and Zn2+. The microbially precipitated shell-like structure grows by lateral or vertical stacking of thin laminae of iron oxide particles which are accreted mostly by fungal filaments. The resulting structures are composed of randomly oriented aggregates of needle-like, uniform-sized crystals, suggesting some biological control in the structure formation. Such structures are formed by the integration of two separated shells, following a complex process driven likely by different strategies of fungal microorganisms that produced the complex macrostructure.

JTD Keywords: Geobiology, Iron oxides, Microbial mineralization


Gustavsson, J., Planell, J., Engel, E., (2013). Ion-selective electrodes to monitor osteoblast-like cellular influence on the extracellular concentration of calcium Journal of Tissue Engineering and Regenerative Medicine 7, (8), 609-620

In bone tissue engineering, the composition of the ionic extracellular environment (IEE) can determine both cellular fate and a biomaterial's development and performance. Therefore, precise control of the IEE and a perfect understanding of the dynamic changes that it can be subject to due to cellular activity is highly desired. To achieve this, we initially monitored how two standard osteoblast-like cell models that expressed either high or low alkaline phosphatase activity - SAOS-2 and MG63 cells, respectively - affected the extracellular concentrations of calcium and phosphate during long-term cultures. It was observed that cellular influence on the IEE varied greatly between the two models and could be linked to the capacity of cells to deposit calcium in the extracellular matrix. Miniaturized ion-selective electrodes that could allow for real-time monitoring of calcium in a minimally invasive way were then constructed. The electrodes were characterized in standard in vitro cell culture environments, prior to being successfully applied for periods of 24h, to record the dynamics of cell-induced deposition of calcium in the extracellular matrix, while using osteogenic media of either high or low concentrations of phosphate. As a result, this study provides the background and technological means for the non-destructive evaluation of the IEE in vitro and allows for the optimization and development of better models of bone tissue construction.

JTD Keywords: Extracellular ions, Ion-selective electrode, MG63, Mineralization, Osteoblasts, Saos-2, Sensor, Tissue engineering


Gustavsson, J., Ginebra, M. P., Planell, J., Engel, E., (2012). Osteoblast-like cellular response to dynamic changes in the ionic extracellular environment produced by calcium-deficient hydroxyapatite Journal of Materials Science-Materials in Medicine , 23, (10), 2509-2520

Solution-mediated reactions due to ionic substitutions are increasingly explored as a strategy to improve the biological performance of calcium phosphate-based materials. Yet, cellular response to well-defined dynamic changes of the ionic extracellular environment has so far not been carefully studied in a biomaterials context. In this work, we present kinetic data on how osteoblast-like SAOS-2 cellular activity and calcium-deficient hydroxyapatite (CDHA) influenced extracellular pH as well as extracellular concentrations of calcium and phosphate in standard in vitro conditions. Since cells were grown on membranes permeable to ions and proteins, they could share the same aqueous environment with CDHA, but still be physically separated from the material. In such culture conditions, it was observed that gradual material-induced adsorption of calcium and phosphate from the medium had only minor influence on cellular proliferation and alkaline phosphatase activity, but that competition for calcium and phosphate between cells and the biomaterial delayed and reduced significantly the cellular capacity to deposit calcium in the extracellular matrix. The presented work thus gives insights into how and to what extent solution-mediated reactions can influence cellular response, and this will be necessary to take into account when interpreting CDHA performance both in vitro and in vivo.

JTD Keywords: Alkaline-phosphatase activity, Saos-2 cells, In-vitro, bone mineralization, Biological basis, Differentiation, Culture, Matrix, Proliferation, Topography