Sodium Fluoride under Dose Range of 2.4–24 μM, a Promising Osteoimmunomodulatory Agent for Vascularized Bone Formation

Abstract

Fluoride has essential effects on bone physiological activity and is widely used in bone biomaterials modification. However, this beneficial effect is highly related to the dose range and improper dosing can lead to pathological conditions such as fluorosis of bone. Therefore, this study first investigated the dose dependent effect of fluoride on bone regeneration. In the range of 0.24–240 μM, in vivo vascularized bone formation can be achieved via fine-tuning the fluoride concentration, and the peak osteogenic effect was found at 2.4–24 μM. The underlying mechanism is related to the modulation of the osteoimmune environment. Fluoride elicited significant osteoimmunomodulatory effect in modulation of the inflammatory cytokines and expression of osteogenic factors (BMP2, OSM, spermine/spermidine) and angiogenic factor (VEGF, IGF-1) during the early response. Fluorine with the doses of 2.4 and 24 μM could increase polyamines and IGF-1 production in macrophages, thus promoting osteogenesis of BMSCs and angiogenesis of HUVECs. These doses could also inhibit the inflammatory response of macrophages. In vitro osteogenesis and angiogenesis were both improved by the fluorine (2.4 and 24 μM)/macrophage conditioned medium, which is consistent with the in vivo results. These results collectively imply that fluoride is an effective osteoimmunomodulatory agent that can regulate both osteogenesis and angiogenesis. “Osteoimmune-smart” bone biomaterials can be developed via incorporating fluorine, and the release concentration should be controlled within the range of 2.4–24 μM for improved bone formation.

Osteoblast/Osteoclast and Immune Cocktail Therapy of an Exosome/Drug Delivery Multifunctional Hydrogel Accelerates Fracture Repair

“…Previous studies have reported that macrophage polarization plays a key role in fracture healing. 27,28 It is welldemonstrated that M2 macrophages are closely related with accelerated clavicle fracture healing in patients with traumatic brain injury (TBI). 29 To verify that the accelerated femoral fracture is also associated with macrophage polarization in TBI mice, we induced concomitant TBI and femoral fracture as well as isolated femoral fracture in mice.…”

Improving hard metal implant and soft tissue integration by modulating the “inflammatory-fibrous complex” response

“…Their hard metal surfaces were prone to form scar tissue via activating cells into fibrillar subtypes in the absence of exogenous signals, unlike soft materials such as hydrogels [ [18] , [19] , [20] ]. Therefore, numerous studies have attempted to inhibit or even eliminate this unsatisfactory inflammatory-fibrous response to guarantee the proper functioning of the metal material [ [21] , [22] , [23] ].…”

The osteoimmunomodulatory effect of nanostructured TiF x /TiO x coating on osteogenesis induction

“…Moreover, fluoride ions at specific concentration have been shown to modulate the macrophage inflammatory response. For instance, a recent study showed that fluoride ions at ultralow and ultrahigh concentrations can activate RAW264.7 macrophages polarized to the M1 phenotype with increased expression of pro-inflammatory genes (interleukin 6 (IL-6) and IL-1β), while a dose range of fluoride ions between 2.4 and 24 µM effectively downregulates M1 markers (inducible nitric oxide synthase (iNOS)) and upregulates M2 markers (arginase (ARG)), which could induce a beneficial osteoimmune environment for bone regeneration [17]. Nevertheless, other reports showed that micromolar fluoride concentrations can reduce the macrophage population and significantly increase the secretion of pro-inflammatory cytokines [18,19].…”