Efficient Single‐Dose Induction of Osteogenic Differentiation of Stem Cells Using Multi‐Bioactive Hybrid Nanocarriers

Abstract

such as limited bone supply, donor site morbidity, risk of infection, or loss of function. [2,3] Synthetic permanent bone substitution grafts are alternative options, however, those show poor osteointegration, may release toxic ions, and present differences in the mechanical properties at the bone/prosthesis interface that can give rise to ruptures. [1,4] Bone tissue engineering offers an alternative approach, with the potential to repair critical size defects and promote bone regeneration. Although different nanomaterials with osteocompatible, osteoconductive, or osteoinductive effects have been previously described in the literature, [5-8] here we propose an original multifunctional approach based on a hybrid silica nanomaterial that can release calcium and phosphate ions intracellularly, and simultaneously deliver a pro-osteogenic substance, dexamethasone (Dex). We hypothesize that the simultaneous intracellular delivery of different stimuli will result in synergistic effects that allow a scaffold-free strategy to induce the differentiation of stem cells into osteoblasts. Silica nanomaterials (and their degradation products) are biocompatible and "generally recognized as safe" (GRAS) by the U.S. Food and Drug Administration (FDA). [9] The degradation rate of silica nanoparticles depends on their size, porosity, and other parameters, [10] and it has been shown that mesoporous silica nanoparticles (MSNs) with 180 nm diameter degraded over 50% in 3 d, and nearly 100% in 7 d. [11] Large size silicabased bioactive materials have been used in orthopedic applications, [12,13] because they are biocompatible, [14] biodegradable, [15] osteoconductive, [16] and even angiogenic. [13,15] Silica released from these materials, together with calcium and phosphate ions, originate both intracellular and extracellular responses that activate the cells in contact with this stimulus. [15,17,18] Previous studies showed how calcium ions stimulate osteoblast proliferation and differentiation, while phosphate ions enhance the rate of bone matrix production by osteogenic cells. [19,20] This spatiotemporally controlled release also induces the formation of a hydroxyapatite layer, which allows bonding to the bone tissue, hence improving osteointegration. [15,21] This process can be greatly improved by using nanosized bioactive materials, which due to their large specific surface area Bone regeneration requires the presence of specific factors to induce the differentiation of stem cells into osteoblasts. These factors induce osteogenesis by stimulating the expression of bone-related proteins, bone cell proliferation and differentiation. Herein, bioactive mesoporous silica nanoparticles are doped with calcium and phosphate ions while the porous network is loaded with dexamethasone (MSN-CaPDex). The bioactive MSN-CaPDex nanocarriers are prepared without affecting the narrow size distribution, pore structure, and morphology of the MSNs, while incorporating multi-stimuli, complementary ionic/biochemical bioactive mediators. The bioactive nano...

Bioactive fluorescent hybrid microparticles as a stand-alone osteogenic differentiation inducer

“…1 C). Similar release kinetics were reported previously for dexamethasone-loaded carriers such as mesoporous silica nanoparticles [ 8 , 17 ] and titanium nanotubes [ 18 ]. Functionalization of PEA to conjugate bioactive molecules has been previously reported [ 19 ] and could be utilized to gain more control on the release rate of the microparticles.…”

“…The sol-gel chemistry provides the possibility of doping the bioactive glasses with different ions to provide cues for desired cell responses. The combined delivery of stimulatory ions of bioactive glasses and osteogenic factor(s) have also been studied to promote bone regeneration [ [6] , [7] , [8] ]. In terms of morphology, particulate morphology specifically provides flexibility for filling bone defects of different shapes and sizes, offers a higher surface area for cell-material interaction, and can be incorporated into injectable formulations.…”

“…Recent studies have shown the ability of BG nanoparticles to direct cells towards osteogenic lineage in the absence of media supplements through the release of different ions such as calcium, phosphate, and strontium ions [ 9 , 10 ]. It has been shown that a single dose of mesoporous silica nanoparticles loaded with dexamethasone and functionalized with calcium and phosphate ions could induce osteogenic differentiation in human bone marrow mesenchymal stem cells [ 8 ]. However, several studies have also reported that silica/bioactive glass particles or their extracts can only enhance osteogenic differentiation of cells in the presence of differentiation media rather than inducing osteogenic differentiation without additional osteogenic supplements [ 11 , 12 ].…”

Platelet lysates-based hydrogels incorporating bioactive mesoporous silica nanoparticles for stem cell osteogenic differentiation

“…The capacity of MSNCaPDex to induce the osteogenic differentiation of hBM-MSCs was already proved in a two-dimensional (2D) study, with several signs of differentiation after 21 d even without additional osteogenic supplementation [ 38 ]. The incorporation and release of Dex and calcium and phosphate ions were also evaluated previously [ 38 , 39 ]. The concentration of bioactive factors released proved to be enough to induce an osteogenic response in hBM-MSCs with a single-dose administration.…”

“…The particles were then dried at 50 °C in a ventilated oven. Afterward, MSNs were functionalized with Ca 2+ and PO 4 3− ions and loaded with Dex to form MSNCaPDex, as described elsewhere [ 38 ]. Briefly, after MSNs dispersion in milli-Q water, solutions of Ca(OH) 2 (0.15 g L −1 ) and DHP (0.10 g L −1 ) were added to the dispersion and the mixture was stirred overnight at RT.…”