Vitamin B9 derivatives as carriers of bioactive cations for musculoskeletal regeneration applications: Synthesis, characterization and biological evaluation

Fernández‐Villa, Daniel; Asensio, Gerardo; Silva, Manuel; Ramírez-Jiménez, Rosa Ana; Saldaña, Laura; Vilaboa, Nuria; Oliveira, Ana L.; Román, Julio San; Vázquez‐Lasa, Blanca; Rojo, Luís

doi:10.1016/j.ejmech.2021.113152

Cited by 5 publications

(16 citation statements)

References 55 publications

(71 reference statements)

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“…In a previous work, SrFO loaded PEGDMA scaffolds were evaluated in vivo in a rat calvaria animal model with induced critical size defects [ 39 ], and results demonstrated that SrFO-containing scaffolds enhanced bone regeneration compared to the control group without strontium. Moreover, the potential used of SrFO as a bone promoting factor has already been tested in vitro with human mesenchymal stem cells demonstrating their ability to modulate by their mRNA profiles towards osteogenic-like or fibrocartilaginous-like phenotypes in basal conditions [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

“…In vitro biocompatibility of the studied system was determined by indirect assay over independent cultures of hOBs and hACs. Results of cell viability in presence of extracts collected over 14 days, reveal that the processed materials do not release any toxic compound during the entire studied time, and even potential benefits can be observed for hOB cells at short and long time points, and for hACs at short time points, probably due to the effect of bioactive SrFO and ZnFO and their capability to promote osteogenic and chondrogenic processes, respectively [ 39 , 40 ], providing a suitable environment for cell proliferation. Confocal microscopy imaging from the different parts of the scaffold revealed the suitability of the system to sustain the colonization of hOB and hAC cells through the whole structure ( Figure 9 ).…”

Section: Discussionmentioning

confidence: 99%

“…The phosphate buffered solution (PBS: NaPO 4 0.01 M, 0.0027 M KCl, 0.137 M NaCl, pH 7.4) was prepared by dissolving tablets, purchased from Fisher BioReagents (Spain), in deionized water, and the remaining solvents purchased from Sigma-Aldrich and used without additional purification. Strontium and zinc folic acid derivatives were obtained as previously reported [ 40 ] with molecular formulas of SrC 19 N 7 O 10 H 25 ·4H 2 O and ZnC 19 N 7 O 10 H 25 ·4H 2 O, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…In the case of bone tissue, one of the most studied agents is β -tricalcium phosphate ( β -TCP), which is a bioceramic that recreates the bone microenvironment of the subchondral region [ 37 ]. In this respect, our research group previously has demonstrated the ability of new strontium and zinc folic acid derivatives (SrFO and ZnFO) to enhance the mechanisms of osteogenesis in vitro and in vivo [ 38 , 39 , 40 ], Additionally, Zn 2+ has been described as a regulatory factor in the degradation of collagen and other components of the extracellular matrix when osteoarthritis is diagnosed [ 41 , 42 ].…”

Section: Introductionmentioning

confidence: 99%

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Biomimetic Gradient Scaffolds Containing Hyaluronic Acid and Sr/Zn Folates for Osteochondral Tissue Engineering

et al. 2021

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Regenerative therapies based on tissue engineering are becoming the most promising alternative for the treatment of osteoarthritis and rheumatoid arthritis. However, regeneration of full-thickness articular osteochondral defects that reproduces the complexity of native cartilage and osteochondral interface still remains challenging. Hence, in this work, we present the fabrication, physic-chemical characterization, and in vitro and in vivo evaluation of biomimetic hierarchical scaffolds that mimic both the spatial organization and composition of cartilage and the osteochondral interface. The scaffold is composed of a composite porous support obtained by cryopolymerization of poly(ethylene glycol) dimethacrylate (PEGDMA) in the presence of biodegradable poly(D,L-lactide-co-glycolide) (PLGA), bioactive tricalcium phosphate β-TCP and the bone promoting strontium folate (SrFO), with a gradient biomimetic photo-polymerized methacrylated hyaluronic acid (HAMA) based hydrogel containing the bioactive zinc folic acid derivative (ZnFO). Microscopical analysis of hierarchical scaffolds showed an open interconnected porous open microstructure and the in vitro behaviour results indicated high swelling capacity with a sustained degradation rate. In vitro release studies during 3 weeks indicated the sustained leaching of bioactive compounds, i.e., Sr2+, Zn2+ and folic acid, within a biologically active range without negative effects on human osteoblast cells (hOBs) and human articular cartilage cells (hACs) cultures. In vitro co-cultures of hOBs and hACs revealed guided cell colonization and proliferation according to the matrix microstructure and composition. In vivo rabbit-condyle experiments in a critical-sized defect model showed the ability of the biomimetic scaffold to promote the regeneration of cartilage-like tissue over the scaffold and neoformation of osteochondral tissue.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Biomimetic Gradient Scaffolds Containing Hyaluronic Acid and Sr/Zn Folates for Osteochondral Tissue Engineering

et al. 2021

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“…In this regard, our research group has prepared metallic complexes of folic acid with Ca, Sr, Zn, Mg, and Mn, and studied them in the context of musculoskeletal regeneration. As they were shown to upregulate genes related to osteo- and chondrogenesis, as well as to promote physiological processes which are essential during the regeneration of these tissues, they were incorporated into different scaffolds, improving their performance both in vitro and in vivo [ 10 , 11 , 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Development of Methotrexate Complexes Endowed with New Biological Properties Envisioned for Musculoskeletal Regeneration in Rheumatoid Arthritis Environments

Fernández‐Villa

Ramírez-Jiménez

Aranaz

et al. 2022

IJMS

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Methotrexate (MTX) administration is the gold standard treatment for rheumatoid arthritis (RA), but its effects are limited to preventing the progression of the disease. Therefore, effective regenerative therapies for damaged tissues are still to be developed. In this regard, MTX complexes of general molecular formula M(MTX)·xH2O, where M = Sr, Zn, or Mg, were synthesized and physicochemically characterized by TGA, XRD, NMR, ATR–FTIR, and EDAX spectroscopies. Characterization results demonstrated the coordination between the different cations and MTX via two monodentate bonds with the carboxylate groups of MTX. Cation complexation provided MTX with new bioactive properties such as increasing the deposition of glycosaminoglycans (GAGs) and alternative anti-inflammatory capacities, without compromising the immunosuppressant properties of MTX on macrophages. Lastly, these new complexes were loaded into spray-dried chitosan microparticles as a proof of concept that they can be encapsulated and further delivered in situ in RA-affected joints, envisioning them as a suitable alternative to oral MTX therapy.

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A study on Sr/Zn phytate complexes: structural properties and antimicrobial synergistic effects against Streptococcus mutans

Asensio

Hernández‐Arriaga

Martín-del-Campo

et al. 2022

Sci Rep

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Phytic acid (PA) is an abundant natural plant component that exhibits a versatility of applications benefited from its chemical structure, standing out its use as food, packing and dental additive due to its antimicrobial properties. The capacity of PA to chelate ions is also well-established and the formation and thermodynamic properties of different metallic complexes has been described. However, research studies of these compounds in terms of chemistry and biological features are still demanded in order to extend the application scope of PA complexes. The main goal of this paper is to deepen in the knowledge of the bioactive metal complexes chemistry and their bactericide activity, to extend their application in biomaterial science, specifically in oral implantology. Thus, this work presents the synthesis and structural assessment of two metallic phytate complexes bearing the bioactive cations Zn2+ and Sr2+ (ZnPhy and SrPhy respectively), along with studies on the synergic biological properties between PA and cations. Metallic phytates were synthesized in the solid-state by hydrothermal reaction leading to pure solid compounds in high yields. Their molecular formulas were C6H12024P6Sr4·5H2O and C6H12024P6Zn6·6H2O, as determined by ICP and HRES-TGA. The metal coordination bond of the solid complexes was further analysed by EDS, Raman, ATR-FTIR and solid 13C and 31P-NMR spectroscopies. Likewise, we evaluated the in vitro ability of the phytate compounds for inhibiting biofilm production of Streptococcus mutans cultures. Results indicate that all compounds significantly reduced biofilm formation (PA < SrPhy < ZnPhy), and ZnPhy even showed remarkable differences with respect to PA and SrPhy. Analysis of antimicrobial properties shows the first clues of the possible synergic effects created between PA and the corresponding cation in different cell metabolic processes. In overall, findings of this work can contribute to expand the applications of these bioactive metallic complexes in the biotechnological and biomedical fields, and they can be considered for the fabrication of anti-plaque coating systems in the dentistry field.

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Vitamin B9 derivatives as carriers of bioactive cations for musculoskeletal regeneration applications: Synthesis, characterization and biological evaluation

Cited by 5 publications

References 55 publications

Biomimetic Gradient Scaffolds Containing Hyaluronic Acid and Sr/Zn Folates for Osteochondral Tissue Engineering

Biomimetic Gradient Scaffolds Containing Hyaluronic Acid and Sr/Zn Folates for Osteochondral Tissue Engineering

Development of Methotrexate Complexes Endowed with New Biological Properties Envisioned for Musculoskeletal Regeneration in Rheumatoid Arthritis Environments

A study on Sr/Zn phytate complexes: structural properties and antimicrobial synergistic effects against Streptococcus mutans

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