Bone morphogenetic proteins:Relationship between molecular structure and their osteogenic activity

Bone morphogenetic proteins(BMPs)are a family of potent,multifunctional growth factors belonging to transforming growth factor-(TGF-).They are highly conservative in structures.Over 20 members of BMPs with varying functions such as embryogenesis,skeletal formation,hematopoiesis and neurogenesis have been identified in human body.BMPs are unique growth factors that can induce the formation of bone tissue individually.BMPs can induce the differentiation of bone marrow mesenchymal stem cells into osteoblastic lineage and promote the proliferation of osteoblasts and chondrocytes.BMPs stimulate the target cells by specific membrane-bound receptors and signal transduced through mothers against decapentaplegic(Smads)and mitogen activated protein kinase(MAPK)pathways.It has been demonstrated that BMP-2,BMP-4,BMP-6,BMP-7,and BMP-9 play an important role in bone formation.This article focuses on the molecular characterization of BMPs family members,mechanism of osteogenesis promotion,related signal pathways of osteogenic function,relationships between structure and osteogenetic activity,and the interactions among family members at bone formation.

Regulation of TiO_(2) nanoarrays on titanium implants for enhanced osteogenic activity and immunomodulation

The surface topography of implants plays a major role in osteogenesis and immunomodulation.In this study,three types of TiO_(2) nanoarrays including nanorod arrays with a diameter of 45 nm(TiO_(2)-N),nanorod arrays with a diameter of 60 nm(TiO_(2)-N N),and nanocone arrays(TiO_(2)-NW)are prepared on titanium and the behavior of bone marrow stromal cells(BMSCs)and polarization of macrophages are studied.Compared to the planar titanium control,TiO_(2) nanoarrays facilitate osteogenesis of BMSCs and stimulate the pro-healing M2 phenotype.However,adhesion,spreading,proliferation,and osteogenic differentiation of BMSCs are more pronounced on TiO_(2)-N N than both TiO_(2)-N and TiO_(2)-NW.TiO_(2)-NN also produces the best immune microenvironment,while TiO_(2)-NW is more favorable than TiO_(2)-NN from the viewpoint of cell adhesion and spreading of osteoblasts.

Numerical model for evaluating the speckle activity and characteristics of bone tissue under the biospeckle laser system

This paper discusses and studies the composition and characteristics of biospeckle on the surface of bone tissues.We used a laser speckle device to capture biospeckle patterns from fresh pig bone tissue.Traditional speckle activity metrics were used to measure the speckle activity of ex vivo bone tissue over time.Both Gaussian and Lorentzian correlation functions were used to char-acterize the ordered and disordered motion of the bone surface,together with volume scattering,to construct the model.Using the established mathematical model of the spatio-temporal evo-lution of the biospeckle pattern,it is possible to account for the presence of volume scattering from the biospeckle of bones,quantify the ordered or disordered motions in the biological speckle activity at the current time,and assess the ability of laser speckle correlation technique to determine biological activity.

Constructing osteo-inductive bio-ink for 3D printing through hybridization of gelatin with maleic acid modified bacterial cellulose by regulating addition volumes of maleic acid solution

Bacterial cellulose(BC)is an exopolysaccharide with unique properties that has been applied in various fields.However,the dense and intertwined nature of BC fibers limits its use in certain applications,including 3D printing scaffolds for bone regeneration.In this work,a controllable BC-based bio-ink for 3D printing was successfully prepared by modifying the neat BC through maleic acid(MA)treatment,aiming to promote bone tissue regeneration.To achieve homogeneous BC dispersions while preserving its crystalline and chemical properties,BC was modified by MA solution(60%,w/V)with solid-liquid ratio from 1꞉5 to 1꞉50(w/V)to obtain MA-BC dispersions.The analysis results from microstructure,chemical group,crystallinity,and wettability indicated that the BC/MA solution with ratio of 1꞉30 demonstrated the best pre-treatment performance to obtain MA-BC.Subsequently,by combining MA-BC with gelatin,we successfully formulated MA-BC-GEL gels with favorable rheological properties and compression modulus,which can be used as promising bio-inks for 3D bioprinting applications.In vitro tests demonstrated 1꞉30 MA-BC possessed excellent biocompatibility,a significant ability to express the alkaline phosphatase gene and osteogenic-related genes,and facilitated the formation of mineralized nodules.The utilization of this novel bio-ink in scaffold preparation for bone regeneration highlights the promising application of modified BC in bone tissue engineering field.

Hyaluronic acid facilitates bone repair effects of calcium phosphate cement by accelerating osteogenic expression

Calcium phosphate cements(CPC)are widely anticipated to be an optimum bone repair substitute due to its satisfied biocompatibility and degradability,suitable to be used in minimally invasive treatment of bone defects.However the clinical application of CPC is still not satisfied by its poor cohesiveness and mechanical properties,in particular its osteoinductivity.Hyaluronic acid reinforced calcium phosphate cements(HA/CPC)showed extroadinary potential not only enhancing the compressive strength of the cements but also significantly increasing its osteoinductivity.In our study,the compressive strength of HA/CPC increased significantly when the cement was added 1%hyaluronic acid(denoted as 1-HA/CPC).In the meantime,hyaluronic acid obviously promoted ALP activity,osteogenic related protein and mRNA expression of hBMSCs(human bone marrow mesenchymal stem cells)in vitro,cement group of HA/CPC with 4%hyaluronic acid adding(denoted as 4-HA/CPC)showed optimal enhancement in hBMSCs differentiation.After being implanted in rat tibial defects,4-HA/CPC group exhibited better bone repair ability and bone growth promoting factors,comparing to pure CPC and 1-HA/CPC groups.The underlying biological mechanism of this stimulation for HA/CPC may be on account of higher osteogenic promoting factors secretion and osteogenic genes expression with hyaluronic acid incorporation.These results indicate that hyaluronic acid is a highly anticipated additive to improve physicochemical properties and osteoinductivity performance of CPCs for minimally invasive healing of bone defects.

A nano-structured TiO_(2)/CuO/Cu_(2)O coating on Ti-Cu alloy with dual function of antibacterial ability and osteogenic activity

Bacteria-associated infection and poor osseointegration are two main reasons for orthopedic implant failure.Ti-Cu alloy exhibited excellent antibacterial property,but still presented unsatisfied osteogenic activities.Therefore,Ti-Cu alloy was surface modified by an alkali-heat treatment in this paper to improve the osteogenic ability without reduction in antibacterial ability.A TiO_(2)/CuO/Cu_(2)O composite coating with nanostructure was deposited on Ti-Cu alloy.The coating showed increased roughness and great hydrophilicity.Antibacterial tests indicated that the modified Ti-Cu alloy exhibited stronger antibacterial ability against Staphylococcus aureus(S.aureus)than Ti-Cu alloy.Meanwhile,cell experiments demonstrated that the composite coating promoted initial adhesion and spreading of MC3T3-E1 cells,enhanced alkaline phosphatase(ALP)activities as well as extracellular matrix(ECM)mineralization,and significantly upregulated osteogenesis-related gene expressions.It was suggested that the nano-structured TiO_(2)/CuO/Cu_(2)O coating on Ti-Cu alloy might provide a potential strategy for orthopedic implant failure.

Corrosion behavior,antibacterial ability,and osteogenic activity of Zn-incorporated Ni-Ti-O nanopore layers on NiTi alloy

Development of bone fixation devices with excellent corrosion resistance,antibacterial ability,and osteogenic activity is critical for promoting fracture healing.In this study,Zn-incorporated nanopore(NP)layers were prepared on the NiTi alloy through anodization and hydrothermal treatment.Results show that Zn can be evenly incorporated into the NP layers in the form of ZnTiO_(2).The Zn-incorporated samples exhibit good corrosion resistance and significantly reduce Ni^(2+)release.Meanwhile,the samples can continuously release Zn^(2+),which is responsible for excellent long-term antibacterial ability.Furthermore,the synergetic effect of Zn^(2+) release and nanoporous structure of the NP layers endues the NiTi alloy excellent osteogenic activity,as verified by upregulated alkaline phosphatase activity,secretion of type I collagen,and extracellular matrix mineralization.Therefore,Zn-incorporated Ni-Ti-O NP layers have great potential as biomedical coatings of NiTi-based implant materials.

Regulating the bioactivity of non-glycosylated recombinant human bone morphogenetic protein-2 to enhance bone regeneration

Recombinant human bone morphogenetic protein-2(rhBMP-2)is the predominant growth factor that effectively induces osteogenic differentiation in orthopedic procedures.However,the bioactivity and stability of rhBMP-2 are intrinsically associated with its sequence,structure,and storage conditions.In this study,we successfully determined the amino acid sequence and protein secondary structure model of non-glycosylated rhBMP-2 expressed by an E.coli expression system through X-ray crystal structure analysis.Furthermore,we observed that acidic storage conditions enhanced the proliferative and osteoinductive activity of rhBMP-2.Although the osteogenic activity of non-glycosylated rhBMP-2 is relatively weaker compared to glycosylated rhBMP-2;however,this discrepancy can be mitigated by incorporating exogenous chaperone molecules.Overall,such information is crucial for rationalizing the design of stabilization methods and enhancing the bioactivity of rhBMP-2,which may also be applicable to other growth factors.

Osteogenic peptides in collagen hydrolysates:Stimulate differentiation of MC3T3-E1 cells viaβ1 integrin-FAK-ERK1/2 signaling pathway and Smad1 protein

Our previous study demonstrated that orally administration of collagen hydrolysates from silver carp skin(SCH)could increase bone remodeling in chronologically aged mice.However,the active compounds and molecular mechanism were still unclear.In this study,SCH showed strong activity in promoting osteogenic differentiation of MC3T3-E1 cells and the active components in it were separated by ultrafiltration and YMC ODS-A C18 column.And then,a series of peptides containing potential osteogenic sequences were identified by LC-MS/MS and two novel peptides,GARGDKGETGEAGE(GE-14)and TGPRGPVGPA(TA-10),were synthesized for further investigation.The results indicated that peptides GE-14 and TA-10 could promote the differentiation and mineralization of MC3T3-E1 cells by positively regulatingβ1 integrin-FAK-ERK1/2 and Smad1 pathway,which might be due to the RGD or GPR sequences in them.These findings suggest that SCH has the potential to be developed as an effective diet supplement to prevent osteoporosis.

Multifunctionalized carbon-fiber-reinforced polyetheretherketone implant for rapid osseointegration under infected environment

Carbon fiber reinforced polyetheretherketone(CFRPEEK)possesses a similar elastic modulus to that of human cortical bone and is considered as a promising candidate to replace metallic implants.However,the bioinertness and deficiency of antibacterial activities impede its application in orthopedic and dentistry.In this work,titanium plasma immersion ion implantation(Ti-PⅢ)is applied to modify CFRPEEK,achieving unique multi-hierarchical nanostructures and active sites on the surface.Then,hybrid polydopamine(PDA)@ZnO-EDN1 nanoparticles(NPs)are introduced to construct versatile surfaces with improved osteogenic and angiogenic properties and excellent antibacterial properties.Our study established that the modified CFRPEEK presented favorable stability and cytocompatibility.Compared with bare CFRPEEK,improved osteogenic differentiation of rat mesenchymal stem cells(BMSCs)and vascularization of human umbilical vein endothelial cells(HUVECs)are found on the functionalized surface due to the zinc ions and EDN1 releasing.In vitro bacteriostasis assay confirms that hybrid PDA@ZnO NPs on the functionalized surface provided an effective antibacterial effect.Moreover,the rat infected model corroborates the enhanced antibiosis and osteointegration of the functionalized CFRPEEK.Our findings indicate that the multilevel nanostructured PDA@ZnO-EDN1 coated CFRPEEK with enhanced antibacterial,angiogenic,and osteogenic capacity has great potential as an orthopedic/dental implant material for clinical application.

Construction of a magnesium hydroxide/graphene oxide/hydroxyapatite composite coating on Mg-Ca-Zn-Ag alloy to inhibit bacterial infection and promote bone regeneration

The improved corrosion resistance, osteogenic activity, and antibacterial ability are the key factors for promoting the large-scale clinical application of magnesium (Mg)-based implants. In the present study, a novel nanocomposite coating composed of inner magnesium hydroxide, middle graphene oxide, and outer hydroxyapatite (Mg(OH)_(2)/GO/HA) is constructed on the surface of Mg-0.8Ca-5Zn-1.5Ag by a combined strategy of hydrothermal treatment, electrophoretic deposition, and electrochemical deposition. The results of material characterization and electrochemical corrosion test showed that all the three coatings have high bonding strength, hydrophilicity and corrosion resistance. In vitro studies show that Mg(OH)2 indeed improves the antibacterial activity of the substrate. The next GO and GO/HA coating procedures both promote the osteogenic differentiation of MC3T3-E1 cells and show no harm to the antibacterial activity of Mg(OH)2 coating, but the latter exhibits the best promoting effect. In vivo studies demonstrate that the Mg alloy with the composite coating not only ameliorates osteolysis induced by bacterial invasion but also promotes bone regeneration under both normal and infected conditions. The current study provides a promising surface modification strategy for developing multifunctional Mg-based implants with good corrosion resistance, antibacterial ability and osteogenic activity to enlarge their biomedical applications.

Improving exposure of anodically ordered Ni-Ti-O and corrosion resistance and biological properties of NiTi alloys by substrate electropolishing

Although Ni-Ti-O nanopores(NPs) can be fabricated by anodization of mechanically polished NiTi alloys, the top disordered layer is difficult to remove thus hindering the functionality of the Ni-Ti-O NPs. In this work, an electropolishing(EP) pretreatment was performed on the NiTi substrate prior to anodization to thoroughly expose the NPs. Our results show that the EP pretreatment for 5 min perfectly removes the top disordered layer on the Ni-Ti-O NPs to expose the underlying NPs and consequently, the corrosion resistance and antibacterial ability are enhanced. The exposed NPs can elongate bone marrow mesenchymal stem cells, which may be responsible for the upregulated alkaline phosphatase activity, secretion of Type I collagen, and extracellular matrix mineralization. These results suggest that EP is a desirable pretreatment before anodization of the NiTi alloys because the irregular surface layer on the Ni-Ti-O NPs can be removed to enhance the corrosion resistance and biological functions.

The use of bioactive peptides to modify materials for bone tissue repair

It has been well recognized that the modification of biomaterials with appropriate bioactive peptides could further enhance their functions.Especially,it has been shown that peptide-modified bone repair materials could promote new bone formation more efficiently compared with conventional ones.The purpose of this article is to give a general review of recent studies on bioactive peptide-modified materials for bone tissue repair.Firstly,the main peptides for inducing bone regeneration and commonly used methods to prepare peptide-modified bone repair materials are introduced.Then,current in vitro and in vivo research progress of peptide-modified composites used as potential bone repair materials are reviewed and discussed.Generally speaking,the recent related studies have fully suggested that the modification of bone repair materials with osteogenicrelated peptides provide promising strategies for the development of bioactive materials and substrates for enhanced bone regeneration and the therapy of bone tissue diseases.Furthermore,we have proposed some research trends in the conclusion and perspectives part.