Abrogation of the inflammatory response in LPS‐stimulated RAW 264.7 murine macrophages by Zn‐ and Cu‐doped bioactive sol–gel glasses

Abstract

The attenuation of an in vitro inflammatory response in RAW 264.7 murine macrophages stimulated with lipopolysaccharide (LPS) endotoxin was tested using sol-gel-derived bioactive glasses. Three general types of sol-gel-derived samples were evaluated: 58S, zinc-containing glasses, and copper-containing glasses. Distinct experimental procedures were used to test the potential of bioactive glasses to attenuate the inflammatory response in three situations: (1) therapeutically following LPS stimulation, (2) prophylactically before LPS stimulation of macrophages, and (3) indirectly via the glass dissolution products after stimulation with LPS. A sandwich enzyme-linked immunosorbent assay (ELISA) was used to monitor the concentration of tumor necrosis factor-alpha (TNF-alpha) secreted by macrophage cells. The strongest reduction in TNF-alpha concentration was observed when macrophage cells were first incubated with bioactive glass powder and then stimulated with LPS. This suggests a possible prophylactic application of these bioactive glasses for the prevention of inflammation. The 58S glass was capable of reducing the expression of TNF-alpha by macrophages, although the zinc- and copper-containing were more effective at suppressing the inflammatory response. The additional benefit of using zinc- and copper-doped bioactive glasses may be explained by the direct interactions of zinc and copper ions in key regulatory pathways for the inflammation response.

PDLLA scaffolds with Cu‐ and Zn‐doped bioactive glasses having multifunctional properties for bone regeneration

“…Cu + 2 and Zn + 2 ions were released from the composites with the same tendencies as in pure doped glass particles as described elsewhere . The different release profile and higher release of Cu + 2 than Zn + 2 ions from either pure doped glass particles or composite scaffolds are due to their differences in atomic radii and electronegativities generating diverse interactions with the nonbridging oxygen of the silicate tetrahedrons from the glass network . Indeed, while Zn can strongly bind to the silicate network forming tetrahedral structures similar as Si atoms hindering its release, no evidence of CuOSi or other connections of Cu to the glass network have been found .…”

“…Zn is an essential trace element in the body playing a critical role in various functions such as the synthesis of nucleic acids (DNA and RNA) . Zn further inhibits osteoclast differentiation, regulates local secretion/expression of osteogenic markers (e.g., alkaline phosphatase, ALP) in bone formation, and shows anti‐inflammatory and antibacterial effects . Cu, conversely, is essential for human life forming part in enzymes of great importance for the proper function of the body .…”

“…Cu has been investigated as an angiogenic agent, as it stimulates the expression of pro‐angiogenic growth factors (i.e., Vascular endothelial growth factor [VEGF]), enhancing in vivo angiogenesis, and stimulating human endothelial cell proliferation . Either Cu or Zn have been incorporated into various materials such as polymers and ceramics for biomedical applications showing antibacterial and angiogenic properties, and a role in collagen deposition, cellular activity, and proliferation of osteoblasts . For instance, Zn has been incorporated into different BG as recently reviewed by Balasubramanian et al Recently, our research group prepared Cu‐ and Zn‐doped glasses by sol‐gel, showing apatite formation after immersion in simulated body fluid, cytocompatibility, and antibacterial properties .…”

Sol–gel synthesis and in vitro bioactivity of copper and zinc-doped silicate bioactive glasses and glass-ceramics

“…In sample with low amount of metal (1Zn-NaBG), an initial fast release followed by a stabilization at long times is observed meanwhile in samples with the highest amount of Zn (5Zn-NaBG and 10Zn-NaBG) a gradual release is displayed. The differences between the release of Cu +2 and Zn +2 ions from 58S and NaBG glasses could be due to differences in atomic radii and electronegativities of these metals generating different interactions with the nonbridging oxygen of the silicate tetrahedrons [11,54]. For instance, as discussed above, Zn can strongly bind to the vitreous network forming tetrahedral structures as similar as Si, diminishing its release [35] whereas no evidence of Cu-O-Si bond formation and no connection of the Cu to the glass network has been found [57].…”

“…Zn is an important trace element in the body playing a critical role in various functions such as the synthesis of nucleic acids (DNA and RNA). Furthermore, Zn inhibits osteoclast differentiation, plays an important role in the bone formation and shows anti-inflammatory and anti-bacterial effects [7,8,[10][11][12][13][14]. The incorporation of Zn into bioactive glasses produces higher chemical stability and densification of glasses matrices [15].…”