infections, and biochemical disorders could be addressed with a wide variety of bone substitutes or implants. [1] Bone is a mineralized composite of inorganic and organic units, mostly hydroxyapatite (HA) and type I collagen, respectively. [2] To mimic the nature of bone, scientists have researched several aspects of the biomaterials of bone substitutes or implants over the past decades, [3] and chemical composition of them is a primary consideration. Currently, magnesium (Mg 2+ ) and Mg 2+ alloys are gaining increasing research interest due to their promising merits, such as biodegradability, relatively slow corrosion rates, and suitable mechanical properties. [4] However, the osteoinductive effect of Mg 2+ alloys could not be directly determined due to complex alloy constituents, complicated surface modification technology, and intricate physiological microenvironments.A bone mineral precursor, amorphous calcium phosphate (ACP), could be fabricated with Mg 2+ ions, which act as an ACP phase stabilizer to maintain a noncrystal phase. [5] Mg 2+ could partially substitute Ca 2+ ions in the apatite structure and inhibit ACP transformation into HA. [5a] Chemically, it has been shown that Mg 2+ ions retard the crystallization of ACP and control the final aging of crystals. [5c] Moreover, Mg 2+ is considered the main intracellular antagonist of Ca 2+ . [6] Hence, there is an unreasonable paradox that Mg 2+ exerts its role during bone formation as an indispensable element due to its inhibitory effects on biomineralization, which were ignored by previous studies. [6,7] Thus, logically, Mg 2+ is proposed to have a complicated connection with osteogenesis.To answer this question derived from the field of regenerative and bioengineering medicine, the best approach is to investigate development, which could subsequently guide regeneration. [2,8] Mineralization development is a kind of complex chemical reaction among calcium (Ca 2+ ), phosphate (PO 4 3− ), Mg 2+ , and some amino acids. [2] Among the bones in vertebrates, the cranial bone is unique because it provides spaces, support, and protection for soft brain tissues, and has two different developmental mechanisms, namely, endochondral and intramembranous ossification. [9] Therefore, the development of the skull is a proper model. [10] Numerous studies have demonstrated that several kinds of factors play explicit roles during cranial development, [8,9,11] but which elements and how these elements influence the formation and mineralization of the skull, in particular, HA and type I collagen, are not well defined.Magnesium (Mg 2+ ), as a main component of bone, is widely applied to promote bone growth and regeneration. However, Mg 2+ can chemically inhibit the crystallization of amorphous calcium phosphate into hydroxyapatite (HA). The underlying mechanisms by which Mg 2+ improves bone biomineralization remain elusive. Here, it is demonstrated that Mg 2+ plays dual roles in bone biomineralization from a developmental perspective. During embryonic development, the Mg 2+ ...
Macrophage activation determines the fate of biomaterials implantation. Though researches have shown that fibronectin (FN) is highly involved in integrin-induced macrophage activation on biomaterials, the mechanism of how nanosized structure affects macrophage behavior is still unknown. Here, titanium dioxide nanotube structures with different sizes are fabricated to investigate the effects of nanostructure on macrophage activation. Compared with larger sized nanotubes and smooth surface, 30 nm nanotubes exhibit considerable lesser pro-inflammatory properties on macrophage differentiation. Confocal protein observation and molecular dynamics simulation show that FN displays conformation changes on different nanotubes in a feature of "size-confined," which causes the hiding of Arg-Gly-Asp (RGD) domain on other surfaces. The matching size of nanotube with FN allows the maximum exposure of RGD on 30 nm nanotubes, activating integrin-mediated focal adhesion kinase (FAK)-phosphatidylinositol-3 kinase 𝜸 (PI3K𝜸) pathway to inhibit nuclear factor kappa B (NF-𝜿B) signaling. In conclusion, this study explains the mechanism of nanostructural-biological signaling transduction in protein and molecular levels, as well as proposes a promising strategy for surface modification to regulate immune responses on bioimplants.
Background In the past few decades, very little research has been carried out to modify implant surfaces to improve osteointegration through the regulation of immune cells. Purpose The aim of this study is to investigate whether the poly(dopamine) (pDA)‐assisted immobilization of IL4 on titanium surfaces could modulate the inflammatory profile of macrophages in vitro and search for the possibility of enhancing implant integration in this way. Material and Methods The surface composition, topography, and roughness of SLA, SLA‐pDA, and SLA‐pDA‐IL4 discs were examined by scanning electron microscope (SEM) and energy dispersive spectrometer (EDS). Then the releasing profile of the SLA‐pDA‐IL4 implants was recorded for 1 week and the bioactivity of released IL4 was investigated by ELISA. Then macrophage polarization was investigated via three methods including: (a) surface marker via immunofluorescence; (b) mRNA levels of M1 and M2 polarization markers via real‐time PCR, and (c) cytokine release via ELISA. Results SEM and EDS revealed that pDA and IL4 were coated successfully on SLA surfaces. The ELISA results showed that IL4 remained its bioactivity on SLA surface and were immobilized on the SLA surface. The immobilization of IL4 through pDA has no significant influence on the attachment, morphology, and proliferation of macrophages, while it increased the M2/M1 proportion in human macrophages revealed by immunofluorescence. The real‐time PCR and ELISA results demonstrated that SLA‐pDA‐IL4 surface reduced the pro‐inflammatory profile compared with SLA‐pDA and SLA surfaces. Conclusions The SLA‐pDA‐IL4 surfaces described here is able to activate adherent macrophages into M2 phenotype and reduce the release of pro‐inflammatory cytokines. Immobilization of IL4 via pDA is convenient and effective, thus providing an applicable way to control macrophage behavior upon implant insertion and is anticipated to accelerating further bone integration.
Implants are widely used in medical applications and yet macrophage-mediated foreign body reactions caused by implants severely impact their therapeutic effects. Although the extensive use of multiple surface modifications has been introduced to provide some mitigation of fibrosis, little is known about how macrophages recognize the stiffness of the implant and thus influence cell behaviors. Here, we demonstrated that macrophage stiffness sensing leads to differential inflammatory activation, resulting in different degrees of fibrosis. The potential mechanism for macrophage stiffness sensing in the early adhesion stages tends to involve cell membrane deformations on substrates with different stiffnesses. Combining theory and experiments, we show that macrophages exert traction stress on the substrate through adhesion and altered membrane curvature, leading to the uneven distribution of the curvature-sensing protein Baiap2, resulting in cytoskeleton remodeling and inflammation inhibition. This study introduces a physical model feedback mechanism for early cellular stiffness sensing based on cell membrane deformation, offering perspectives for future material design and targeted therapies.
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