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Although silicon is a widespread constituent in dental materials, its possible influence on the formation and repair of teeth remains largely unexplored. Here, we studied the effect of two silicic acid-releasing nanomaterials, silica and bioglass, on a living model of pulp consisting of dental pulp stem cells seeded in dense type I collagen hydrogels. Silica nanoparticles and released silicic acid had little effect on cell viability and mineralization efficiency but impacted metabolic activity, delayed matrix remodeling, and led to heterogeneous cell distribution. Bioglass improved cell metabolic activity and led to a homogeneous dispersion of cells and mineral deposits within the hydrogel. These results suggest that the presence of calcium ions in bioglass is not only favorable to cell proliferation but can also counterbalance the negative effects of silicon. Both chemical and biological processes should therefore be considered when investigating the effects of silicon-containing materials on dental tissues.

Based on stem cell injection into degenerated Nucleus Pulposus (NP), novel treatments for intervertebral disc (IVD) regeneration were disappointing because of cell leakage or inappropriate cell differentiation. In this study, we hypothesized that mesenchymal stromal cells encapsulated within injectable hydrogels possessing adequate physico-chemical properties would differentiate into NP like cells. Composite hydrogels consisting of type I collagen and tyramine-substituted hyaluronic acid (THA) were prepared to mimic the NP physico-chemical properties. Human bone marrow derived mesenchymal stromal cells (BM-MSCs) were encapsulated within hydrogels and cultivated in proliferation medium (supplemented with 10% fetal bovine serum) or differentiation medium (supplemented with GDF5 and TGFβ1) over 28 days. Unlike pure collagen, collagen/THA composite hydrogels were stable over 28 days in culture. In proliferation medium, the cell viability within pure collagen hydrogels was high, whereas that in composite and pure THA hydrogels was lower due to the weaker cell adhesion. Nonetheless, BM-MSCs proliferated in all hydrogels. In composite hydrogels, cells exhibited a rounded morphology similar to NP cells. The differentiation medium did not impact the hydrogel stability and cell morphology but negatively impacted the cell viability in pure collagen hydrogels. A high THA content within hydrogels promoted the gene expression of NP markers such as collagen II, aggrecan, SOX9 and cytokeratin 18 at day 28. The differentiation medium potentialized this effect with an earlier and higher expression of these NP markers. Taken together, these results show that the physico-chemical properties of collagen/THA composite hydrogels and GDF5/TGFβ1 act in synergy to promote the differentiation of BM-MSCs into NP like cells.

The elaboration of scaffolds able to efficiently promote cell differentiation toward a given cell type remains challenging. Here, we engineered dense type I collagen threads with the aim of providing scaffolds with specific morphological and mechanical properties for C3H10T1/2 mesenchymal stem cells. Extrusion of pure collagen solutions at different concentrations (15, 30, and 60 mg/mL) in a PBS 5× buffer generated dense fibrillated collagen threads. For the two highest concentrations, threads displayed a core–shell structure with a marked fibril orientation of the outer layer along the longitudinal axis of the threads. Young’s modulus and ultimate tensile stress as high as 1 and 0.3 MPa, respectively, were obtained for the most concentrated collagen threads without addition of any cross-linkers. C3H10T1/2 cells oriented themselves with a mean angle of 15–24° with respect to the longitudinal axis of the threads. Cells penetrated the 30 mg/mL scaffolds but remained on the surface of the 60 mg/mL ones. After three weeks of culture, cells displayed strong expression of the tendon differentiation marker Tnmd, especially for the 30 mg/mL threads. These results suggest that both the morphological and mechanical characteristics of collagen threads are key factors in promoting C3H10T1/2 differentiation into tenocytes, offering promising levers to optimize tissue engineering scaffolds for tendon regeneration.

Cells respond to biophysical and biochemical signals. We developed a composite filament from collagen and silica particles modified to interact with collagen and/or present a laminin epitope (IKVAV) crucial for cell–matrix adhesion and signal transduction. This combines scaffolding and signaling and shows that local tuning of collagen organization enhances cell differentiation.

The craniofacial area is prone to trauma or pathologies often resulting in large bone damages. One potential treatment option is the grafting of a tissue‐engineered construct seeded with adult mesenchymal stem cells (MSCs). The dental pulp appears as a relevant source of MSCs, as dental pulp stem cells display strong osteogenic properties and are efficient at bone formation and repair. Fibroblast growth factor‐2 (FGF‐2) and/or hypoxia primings were shown to boost the angiogenesis potential of dental pulp stem cells from human exfoliated deciduous teeth (SHED). Based on these findings, we hypothesized here that these primings would also improve bone formation in the context of craniofacial bone repair. We found that both hypoxic and FGF‐2 primings enhanced SHED proliferation and osteogenic differentiation into plastically compressed collagen hydrogels, with a much stronger effect observed with the FGF‐2 priming. After implantation in immunodeficient mice, the tissue‐engineered constructs seeded with FGF‐2 primed SHED mediated faster intramembranous bone formation into critical size calvarial defects than the other groups (no priming and hypoxia priming). The results of this study highlight the interest of FGF‐2 priming in tissue engineering for craniofacial bone repair. Stem Cells Translational Medicine2019;8:844&857 Priming stem cells from human exfoliated deciduous teeth with fibroblast growth factor‐2 within plastically compressed collagen hydrogels improves osteoformation in vivo in the context of craniofacial bone repair with a faster intramembranous bone formation into calvarial bone critical size defects when compared with either of the 2 other groups (no priming and hypoxia priming) that produced smaller amounts of new bone.

Cutaneous chronic wounds remain a major clinical challenge which requires the development of novel wound dressings. Previously, we showed that collagen–silica nanocomposites consisting of polyethyleneimine (PEI)-DNA complexes associated with silica nanoparticles (SiNP), collagen hydrogel and 3T3 fibroblasts, can work as a local “cell factory”. Indeed, the “in-gel” transfection leads to a sustained production and release of biomolecules. Herein, we further explored the possibility for nanocomposites to deliver interleukin-10 (IL-10), a potent anti-inflammatory cytokine, which favors tissue repair. Its anti-inflammatory effect was evaluated in an in vitroinflammation model carried out by LPS (lipopolysaccharide) activation of macrophages embedded in collagen gel. The IL-10 synthesis from nanocomposites was detected over one week in the range of 200–400 pg mL−1and reached a maximum at day 5 without any observed cytotoxic effects. PEI10-SiNP outperformed free PEI10and PEI25-SiNP, implying that the introduction of SiNP improved the transfection efficiency of low Mwof PEI. In addition, the structure and mechanical properties of collagen–silica nanocomposites were stable over one week. Subsequently, the ability of nanocomposites to modulate inflammation was tested in a 3D model of inflammation. The decrease of TNF-α and IL-1β gene expression by 20–80% indicated successful inhibition of inflammation by IL-10 released from nanocomposites. Taken together, the nanocomposites are capable of producing effective doses of IL-10 which inhibit the synthesis of pro-inflammatory cytokines and favor the expression of wound healing cytokines. Therefore, the as-constructed 3D gene delivery system represents a promising strategy for the controlled release of therapeutic biomolecules favoring cutaneous wound healing.

Local delivery of biomolecules from hydrogels is highly challenging because of their rapid diffusion and degradation. Gene therapy represents an alternative that allows for the prolonged production of proteins by transfected cells. In this study, we have developed nanocomposites consisting of DNA-polyethylenimine-silica nanoparticle complexes coencapsulated with fibroblasts within collagen hydrogels. Through the modulation of the particle size and polyethylenimine molecular weight, it was possible to achieve “in-gel” transfection permitting the sustained production of biomolecules from hydrogels over 1 week. Alternative configurations consisting of particle addition to cellularized gels and cell culture in the presence of complex-containing hydrogels were also investigated. These studies demonstrated that particle encapsulation limits DNA and silica dissemination outside the collagen hydrogels. They also show the key role of cell proliferation within collagen hydrogels on the transfection efficiency. Such nanocomposites therefore constitute promising materials for the development of novel gene delivery systems to promote tissue repair.

A model of the fate of colloidal silica in the dermis was designed based on the diffusion of fluorescent silica nanoparticles through collagen hydrogels. The diffusion process was found to depend on particle size (10–200 nm) and surface charge, as well as on collagen concentration (1.5–5 mg mL−1). The presence of human dermal fibroblasts within the hydrogels also significantly impacted on the behaviour of the particles. In particular, the simultaneous monitoring of particulate and soluble forms of silica showed that both the hydrogel network and the cellular activity have a strong influence on the solubilization process of the silica particles, through a combination of surface sorption, uptake and intracellular dissolution. Interactions between silica and collagen in 3D environments also lower the cytotoxicity of 10 nm particles compared to traditional 2D cultures. The results emphasize the complexity of silica chemistry in living tissues and specifically indicate the need for further investigations of the in vivobehaviour of its soluble forms.

A buffer‐mediated gelation route for collagen hydrogels that allows the formation of homogeneous composite and hybrid materials with various silica sources (i.e., colloidal silica and soluble silicates) at high concentration (up to 25 × 10−3M) is described. Most significant improvement in rheological properties and proliferation of primary adult human dermal fibroblasts was obtained for the silicate‐based hybrid materials. A similar trend was observed in composite materials incorporating 14 nm SiO2nanoparticles, although to a much lesser extent, whereas larger colloids (80 and 390 nm) did not significantly impact mechanical stability and cell behavior. Modification of 80 nm particles surface with amine groups weakens the collagen‐mineral interface, resulting in the decrease of material stability and leading to particle aggregation during the course of cell proliferation experiments.

Hybrid and nanocomposite silica–collagen materials derived from concentrated collagen hydrogels were evaluated in vitro and in vivo to establish their potentialities for biological dressings. Silicification significantly improved the mechanical and thermal stability of the collagen network within the hybrid systems. Nanocomposites were found to favor the metabolic activity of immobilized human dermal fibroblasts while decreasing the hydrogel contraction. Cell adhesion experiments suggested that in vitro cell behavior was dictated by mechanical properties and surface structure of the scaffold. First-to-date in vivo implantation of bulk hydrogels in subcutaneous sites of rats was performed over the vascular inflammatory period. These materials were colonized and vascularized without inducing strong inflammatory response. These data raise reasonable hope for the future application of silica–collagen biomaterials as biological dressings.

Hybrid nanoparticles have great potential for biotechnological and biomedical applications. It was recently proposed that biopolymer/silica nanomaterials could be easily obtained by adapting traditional routes used in pharmaceutical science to design polymer nanoparticles. In this paper, we demonstrate that core–shell gelatine/silica nanoparticles can be obtained using a nano-emulsion route, taking advantage of the thermal gelation properties of the biopolymer and of its strong “biomimetic” affinity for silicates. The formation of the silica coating could be ascertained by SEM, TEM, EDAX, FTIR and DLS/zeta potential measurements. Silica coating was also performed on microparticles, allowing us to investigate in more detail the mechanism of silica deposition on the gelatine surface, which bears some relevance for the understanding of biosilicification processes. Finally, the possible internalization and intracellular degradation of these hybrid nanoparticles by fibroblast cells was demonstrated. A comparison with previously described silica/alginate nanoparticles is provided in the context of drug-delivery system design.

Several methods have already been developed for the design of (bio)polymer micro- and nanoparticles used in pharmaceutical science. In this paper, we demonstrate that some of these approaches can be easily adapted for the design of hybrid nanocapsules. A microgel route can be used for the synthesis of poly-l-lysine/alginate microparticles, that are further coated with silica, leading to micron sized core shell composites. Alternatively, a spray-drying technique is used for the one-pot synthesis of silica/poly-l-lysine/alginate nanocomposites that exhibit a homogeneous structure. As a consequence, the in situreduction of Co2+ions leads to the intra-capsular formation of magnetic cobalt silicates. When added to fibroblast cells, nanoparticles enter the intracellular space where they are degraded, suggesting that these new nanocomposites should be suitable for targeted drug delivery applications.

The pathophysiology of dilated cardiomyopathy (DCM), one major cause of heart failure, is characterized by the dilation of the heart but remains poorly understood because of the lack of adequate in vitromodels. Current 2D models do not allow for the 3D organotypic organization of cardiomyocytes and do not reproduce the ECM perturbations. In this review, the different strategies to mimic the chemical, physical and topographical properties of the cardiac tissue affected by DCM are presented. The advantages and drawbacks of techniques generating anisotropy required for the cardiomyocytes alignment are discussed. In addition, the different methods creating macroporosity and favoring organotypic organization are compared. Besides, the advances in the induced pluripotent stem cells technology to generate cardiac cells from healthy or DCM patients will be described. Thanks to the biomaterial design, some features of the DCM extracellular matrix such as stiffness, porosity, topography or chemical changes can impact the cardiomyocytes function in vitroand increase their maturation. By mimicking the affected heart, both at the cellular and at the tissue level, 3D models will enable a better understanding of the pathology and favor the discovery of novel therapies.