Elimination of methicillin‑resistant Staphylococcus aureus biofilms on titanium implants via photothermally‑triggered nitric oxide and immunotherapy for enhanced osseointegration

Background:Treatment of methicillin-resistant Staphylococcus aureus(MRSA)biofilm infections in implant placement surgery is limited by the lack of antimicrobial activity of titanium(Ti)implants.There is a need to explore more effective approaches for the treatment of MRSA biofilm infections.Methods:Herein,an interfacial functionalization strategy is proposed by the integration of mesoporous polydopamine nanoparticles(PDA),nitric oxide(NO)release donor sodium nitroprusside(SNP)and osteogenic growth peptide(OGP)onto Ti implants,denoted as Ti-PDA@SNP-OGP.The physical and chemical properties of Ti-PDA@SNP-OGP were assessed by scanning electron microscopy,X-ray photoelectron spectroscope,water contact angle,photothermal property and NO release behavior.The synergistic antibacterial effect and elimination of the MRSA biofilms were evaluated by 2′,7′-dichlorofluorescein diacetate probe,1-N-phenylnaphthylamine assay,adenosine triphosphate intensity,O-nitrophenyl-β-D-galactopyranoside hydrolysis activity,bicinchoninic acid leakage.Fluorescence staining,assays for alkaline phosphatase activity,collagen secretion and extracellular matrix mineralization,quantitative real‑time reverse transcription‑polymerase chain reaction,and enzyme-linked immunosorbent assay(ELISA)were used to evaluate the inflammatory response and osteogenic ability in bone marrow stromal cells(MSCs),RAW264.7 cells and their co-culture system.Giemsa staining,ELISA,micro-CT,hematoxylin and eosin,Masson's trichrome and immunohistochemistry staining were used to evaluate the eradication of MRSA biofilms,inhibition of inflammatory response,and promotion of osseointegration of Ti-PDA@SNP-OGP in vivo.Results:Ti-PDA@SNP-OGP displayed a synergistic photothermal and NO-dependent antibacterial effect against MRSA following near-infrared light(NIR)irradiation,and effectively eliminated the formed MRSA biofilms by inducing reactive oxygen species(ROS)-mediated oxidative stress,destroying bacterial membrane integrity and causing leakage of intracellular components(P<0.01).In vitro experiments revealed that Ti-PDA@SNP-OGP not only facilitated osteogenic differentiation of MSCs,but also promoted the polarization of pro-inflammatory M1 macrophages to the anti-inflammatory M2-phenotype(P<0.05 or P<0.01).The favorable osteo-immune microenvironment further facilitated osteogenesis of MSCs and the anti-inflammation of RAW264.7 cells via multiple paracrine signaling pathways(P<0.01).In vivo evaluation confirmed the aforementioned results and revealed that Ti-PDA@SNP-OGP induced ameliorative osseointegration in an MRSA-infected femoral defect implantation model(P<0.01).Conclusions:Ti-PDA@SNP-OGP is a promising multi-functional material for the high-efficient treatment of MRSA infections in implant replacement surgeries.

Impact of High Sodium Diet on Neovascularization and Osseointegration around Titanium Implant:An in Vivo and in Vitro Study

Objective A high sodium(HS)diet is believed to affect bone metabolism processes.Clarifying its impact on osseointegration of titanium(Ti)implants holds significant implications for postoperative dietary management of implanted patients.Methods This investigation probed the impact of sodium ions(Na^(+))on neovascularization and osteogenesis around Ti implants in vivo,utilizing micro-computed tomography,hematoxylin and eosin staining,and immunohistochemical analyses.Concurrently,in vitro experiments assessed the effects of varied Na^(+)concentrations and exposure durations on human umbilical vein endothelial cells(HUVECs)and MC3T3-E1 cells.Results In vivo,increased dietary sodium(0.8%-6.0%)led to a substantial decline in CD34 positive HUVECs and new bone formation around Ti implants,alongside an increase in inflammatory cells.In vitro,an increase in Na^(+)concentration(140-150 mmol/L)adversely affected the proliferation,angiogenesis,and migration of HUVECs,especially with prolonged exposure.While MC3T3-E1 cells initially exhibited less susceptibility to high Na^(+)concentrations compared to HUVECs during short-term exposure,prolonged exposure to a HS environment progressively diminished their proliferation,differentiation,and osteogenic capabilities.Conclusion These findings suggest that HS diet had a negative effect on the early osseointegration of Ti implants by interfering with the process of postoperative vascularized bone regeneration.

The role of exosomes in bone remodeling and osseointegration of implants

Dental implant is an effective method in the treatment of missing teeth.The process of osseointegration of implant teeth involves the coordinated operation of immune system and bone system.The interaction between cells is closely related to bone formation and repair.Exosomes are important intercellular communication molecules.They were originally found in the supernatant of sheep erythrocytes cultured in vitro.They are micro vesicles with a diameter of 40~150 nm.They exist in a variety of cells and body fluids.They enter the target cells by endocytosis and transport,affecting the expression of cell genes and changing the fate of cells.It has an important regulatory function in the microenvironment of implant bone binding.It plays a role in bone remodeling through small molecular RNA,specific proteins and other growth factors secreted by different cells.This article reviews the role of bone derived cellderived exosomes in bone remodeling and their function in implant osseointegration.

Effect of High Positive Acceleration(+Gz) Environment on Dental Implant Osseointegration:A Preliminary Animal Study

Objective To observe the effect of high positive acceleration(+Gz) environment on dental implant osseointegration in a rabbit model and to investigate its mechanism.Methods Forty-eight New Zealand white rabbits were randomly divided into 6 groups. The rabbit’s mandibular incisors were extracted and 1 implant was placed in each socket immediately. After 1 week of rest, the rabbits were exposed to a high +Gz environment, 3 times a week. The rabbits were sacrificed at 3 weeks(2 weeks +Gz exposure), 5 weeks(4 weeks +Gz exposure), and 12 weeks(4 weeks +Gz exposure and 7 weeks normal environment) after surgery, respectively. Specimens were harvested for micro-CT scanning, histological analysis, and real-time polymerase chain reaction examination.Results Compared with those in the control group, the mRNA expression levels of bone morphogenetic protein-2(BMP-2), osteopontin(OPN), and transforming growth factor-β1(TGF-β1)were significantly lower(P < 0.05), while the mRNA expression level of receptor activator of nuclear factor κB ligand(RANKL) and the RANKL/osteoprotegerin(OPG) ratio were significantly higher(P < 0.05)at 3 weeks;values of bone volume fraction, trabecular number, bone-implant contact(BIC), and TGF-β1 and OPG mRNA expression levels were significantly lower(P < 0.05), and the value of trabecular separation, RANKL mRNA expression level and RANKL/OPG ratio were significantly higher(P < 0.05) at 5 weeks;and the value of BIC was still significantly lower(P < 0.05) at 12 weeks in the experimental group.Conclusion Early exposure to the high +Gz environment after implant surgery might have an adverse effect on osseointegration, and its mechanism could be related to the inhibition of osteoblast activity and promotion of osteoclast activity.

Enhanced Biocompatibility and Osseointegration of Calcium Titanate Coating on Titanium Screws in Rabbit Femur

This study aimed to examine the biocompatibility of calcium titanate(CaTiO3) coating prepared by a simplified technique in an attempt to assess the potential of CaTiO3coating as an alternative to current implant coating materials. CaTiO3-coated titanium screws were implanted with hydroxyapatite(HA)-coated or uncoated titanium screws into medial and lateral femoral condyles of 48 New Zealand white rabbits. Imaging, histomorphometric and biomechanical analyses were employed to evaluate the osseointegration and biocompatibility 12 weeks after the implantation. Histology and scanning electron microscopy revealed that bone tissues surrounding the screws coated with CaTiO3were fully regenerated and they were also well integrated with the screws. An interfacial fibrous membrane layer, which was found in the HA coating group, was not noticeable between the bone tissues and CaTiO3-coated screws. X-ray imaging analysis showed in the CaTiO3coating group, there was a dense and tight binding between implants and the bone tissues; no radiation translucent zone was found surrounding the implants as well as no detachment of the coating and femoral condyle fracture. In contrast, uncoated screws exhibited a fibrous membrane layer, as evidenced by the detection of a radiation translucent zone between the implants and the bone tissues. Additionally, biomechanical testing revealed that the binding strength of CaTiO3coating with bone tissues was significantly higher than that of uncoated titanium screws, and was comparable to that of HA coating. The study demonstrated that CaTiO3coating in situ to titanium screws possesses great biocompatibility and osseointegration comparable to HA coating.

Adhesion-enhancing coating embedded with osteogenesis-promoting PDA/HA nanoparticles for peri-implant soft tissue sealing and osseointegration

Following dental implantation,the characteristic bacterial milieu of the oral cavity may lead to peri-implant inflammation,which can negatively impact osseointegration and cause implant failure.To improve soft tissue sealing around the implant,enhance osseointegration,and improve implant success rates,this paper proposes a composite multifunctional coating(PHG)prepared using gelatin and polydopamine/hydroxyapatite nanoparticles,investigates the effects of this novel coating on cell adhesion,proliferation,antibacterial activity,osteogenic differentiation,and evaluates its immune-related properties.The PHG coating was proved to have satisfactory hydrophilicity and wettability for cell attachment.Furthermore,it improved the expression of adhesion-related genes and proteins in human gingival fibroblasts,indicating its adhesion-promoting effect.Additionally,bone marrow mesenchymal stem cells exhibited strong osteogenic differentiation potential and mineralization on PHG-coated surfaces.Notably,the PHG coating exhibited antibacterial activity against Streptococcus mutans,as well as anti-inflammatory effects,potentially via the regulation of macrophages.Therefore,the proposed PHG coating may promote soft tissue sealing and bone bonding,providing a potential strategy for the surface modification of dental implants.

Early Osseointegration of Implants with Cortex-like TiO2 Coatings Formed by Micro-arc Oxidation:A Histomorphometric Study in Rabbits

In our previous studies, a novel cortex-like Ti O2 coating was prepared on Ti surface through micro-arc oxidation（MAO） by using sodium tetraborate as electrolyte, and the effects of the coating on cell attachment were testified. This study aimed to investigate the effects of this cortex-like MAO coating on osseointegration. A sand-blasting and acid-etching（SLA） coating that has been widely used in clinical practice served as control. Topographical and chemical characterizations were conducted by scanning electron microscopy, energy dispersive X-ray spectrometer, X-ray diffraction, contact angle meter, and step profiler. Results showed that the cortex-like coating had microslots and nanopores and it was superhydrophilic, whereas the SLA surface was hydrophobic. The roughness of MAO was similar to that of SLA. The MAO and SLA implants were implanted into the femoral condyles of New Zealand rabbits to evaluate their in-vivo performance through micro-CT, histological analysis, and fluorescent labeling at the bone-implant interface four weeks after surgery. The micro-CT showed that the bone volume ratio and mean trabecular thickness were similar between MAO and SLA groups four weeks after implantation. Histological analysis and fluorescent labeling showed no significant differences in the bone-implant contact between the MAO and SLA surfaces. It was suggested that with micro/nanostructure and superhydrophilicity, the cortex-like MAO coating causes excellent osseointegration, holding a promise of an application to implant modification.

Evaluation of the osseointegration of dental implants coated with calcium carbonate:an animal study

In an attempt to overcome the limitations of titanium in dental and orthopaedic clinical applications, a new method has been developed to prepare calcium carbonate coatings on sandblasted and acid-etched （SA） titanium implants. The purpose of this study was to investigate the effect of calcium carbonate-SA （CC-SA） implants on osseointegration in vivo. The surfaces of SA and CC-SA implants were characterised for surface morphology and surface chemistry. Subsequently, these two kinds of implants were implanted in the femoral condyles of rabbits. The implants were retrieved and prepared for histological and histomorphometric evaluation 1, 2, 4, 8 and 12 weeks after implantation. Significantly higher values of bone-to-implant contact of the entire implant except the gap area （BIC_ALL） and the bone-to-implant contact of the gap area （BIC_GAP） were found in animals with the CC-SA implants than in those with the SA implants at 4 weeks. Higher values of total gap bone were found in those with the CC-SA implants than in those with the SA implants at 1, 2 and 4 weeks. In conclusion, the current findings demonstrate that the calcium carbonate coating can improve and accelerate the early ingrowth of bone and osseointegration at the early healine phase. This may reduce clinical healinE times and thus improve implant success rates.

Effects of bone morphogenetic protein on the osseointegration of porous-surfaced implants:An experimental study in rabbits

Objective： Research on enhancing early osseointegration of cementless implants to improve early fixation and reducing of risk of loosening. Methods ： Thirty New Zealand rabbits were divided into two groups at random. BMP combined with DBM 30 mg was inserted around the prosthesis in 15 rabbits as experimental group, the remaining rabbits were served as control group. After 4, 8, and 12 weeks, five rabbits were sacrificed in each group. The humerus with the implants were retrieved. Bone ingrowth was analyzed by none-decalcification bone ground section and biomechanical test. Results： At the end of 4 and 8 weeks the osseointegration rates of BMP group were higher than those of control （P 〈 0.05）. The ultimate shear strength between BMP treated implantation and the control was the same as the results in osseointegration rates at 4, 8 weeks （P 〈 0.05）. However, there was no difference between the treated and untreated group in the osseointegration rate and ultimate shear strength at 12 weeks （P 〉 0.05）. Conclusion： BMP combination can enhance bone growth into gaps around cementless implants, especially in the early postoperative period.

Evaluation of titanium dental implants after early failure of osseointegration by means of X-ray photoelectron spectoscopy, electron microscopy and histological studies

In this work, we analysed 56 clinically failed and retrieved implants by means of scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS) and histological studies. The surface contamination was compared to that of unused control implants and with that of the same implants after cleaning in a basic medium. The surfaces of the unused implants presented considerable contamination. In particular, high levels of carbon were detected. The nature of this C was elucidated by XPS analysis of the lubricant used in the machining process. The same contamination was observed in the retrieved implants. Histological studies were carried out by means of light microscopy. Fibrosis and granulomatous lesions were detected in the tissues. XPS analysis indicated the presence of traces of other elements (Na, Ca, Zn, S, F, etc.) that were not related to impurities in cpTi. We examined a cleaning process in a basic medium that eliminates the organic components of the implant surfaces. The cleaned implants were implanted in the patients and the results were excellent. None of the implants failed in following 7 months.

Conformationally regulated“nanozyme-like”cerium oxide with multiple free radical scavenging activities for osteoimmunology modulation and vascularized osseointegration

Given post-operative aseptic loosening in orthopedic disease treatment,osteointegration occurs at the bone-implant interface as a holistic process,including immunoregulation(e.g.,macrophage polarization),angiogenesis and osteogenesis in sequence.In order to achieve early rapid and satisfactory osseointegration,different nano-shaped(nanocone,nanopolyhedron and nanoflower abbr.NC,NP&NF)cerium oxide(CeO_(2-x))coatings,endowed with“nanozyme-like”activities for multiple free radical elimination and osteoimmunology regulation,were hydrothermally synthesized on titanium alloy(TC4).In vitro cell experiments showed that nano-CeO_(2-x) coated TC4 not only induced polarization of RAW264.7 cells toward M2 phenotype,but also promoted angiogenesis and vascularization of endothelial cells along with differentiation and mineralization of osteogenic precursor cells.Improvements in M2-polarized macrophage,angiogenesis,and bone regeneration were further confirmed in a rat femoral condyle model.Among the above three nano-morphologies,NF exhibited the best osseoinetegration.RNA sequencing and mechanism exploration suggested that the inhibition of PI3K-AKT signaling pathway was essential for immunomodulatory capacity of NF.In conclusion,it provided promising insights into the immunomodulatory exploitation of orthopedic implants.

Cobalt ions-derived nanoenzyme array for endosseous neural network reconstruction and osseointegration

Interactions between bone cells and neurocytes are crucial for endosseous nerve and ensuing bone regeneration.However,absence of neural stem cells in bone makes the innervation of implant osseointegration a major challenge.Herein,a nanorod-like array of sodium hydrogen titanate(ST)co-doped with Co^(2+)and Co^(3+),namely STC_(h) that behaves as a reactive oxygen species(ROS)-scavenging enzyme,was hydrothermally formed on Ti substrate.We show that the doped Co^(2+)and Co^(3+)locate at TiO_(6) octahedral interlayers and within octahedra of STC_(h) lattice,appearing releasable and un-releasable,respectively,leading to an increase in Co^(3+)/Co^(2+)ratio and enzyme activity of the array with immersion.The nanoenzyme-released Co^(2+)triggers macrophages(Ms)towards M1 phenotype,then the nanoenzyme scavenges extracellular ROS inducing M1-to-M2 transition.The neurogenic factors secreted by STC_(h)-regulated MΦs,in combination with the released Co^(2+),promote mesenchymal stem cells to differentiate into neurons and Schwann cells compared to sole Co^(2+)and sT.STC_(h) array greatly enhances nerve reconstruction,type-H capillary formation and ensuing osseointegration in normal rat bone,and antibacteria via engulfing S.aureus by MΦs and osteogenesis in infective case.This nanoenzyme provides an alternative strategy to orchestrate endosseous nerve regeneration for osseointegration without loading exogenous neurotrophins in implants.

Vancomycin-encapsulated hydrogel loaded microarc-oxidized 3D-printed porous Ti6Al4V implant for infected bone defects:Reconstruction,anti-infection,and osseointegration

Infected bone defect is a formidable clinical challenge.Conventional approaches to prevention and treatment for infected bone defects are unsatisfactory.The key elements of the treatment are bone defect reconstruction,antiinfection,and osteogenesis.Conventional treatment methods remain unsatisfactory owing to the absence of composite integrating materials with anti-infective,and osteogenic activities as well as proper mechanical strength at the same time.In this study,we fabricated a vancomycin-encapsulated hydrogel with bacteriaresponsive release properties combined with a shaved porous(submicron-micron)three-dimensional-printed Ti6Al4V implant.The implant surface,modified with submicron-sized pores through microarc oxidation(MAO),showed enhanced osteogenic activity and integrated well with the hydrogel drug release system,enabling sustained vancomycin release.In vitro experiments underscored the commendable antibacterial ability,biosafety,and osteoinductive potential.Effective antibacterial and osteogenic abilities of the implant were further demonstrated in vivo in infected rabbit bone defects.These results showed that the vancomycinencapsulated hydrogel-loaded microarc-oxidized 3D-printed porous Ti6Al4V can repair the infected bone defects with satisfactory anti-infection and osseointegration effects.

Surface modification of titanium implant for repairing/improving microenvironment of bone injury and promoting osseointegration

Bone injury and implantation operation are often accompanied by microenvironment damage of bone tis-sue,which seriously affects the process of osseointegration of implants,especially for titanium(Ti)-based bioinert materials.Thus,repairing or improving the microenvironment of damaged bone tissue is of great significance for bone rescue,reconstruction,and regeneration,which is still a major medical challenge.Oxidative stress(OS)and oxygen(O_(2))deficiency are considered to be specific physiological signals of the bone-injury microenvironment.From the above background,a coating consisting of manganese dioxide(MnO_(2))nanoenzyme and strontium(Sr)ions was fabricated on the surface of the Ti implant via a one-step hydrothermal treatment.MnO_(2) nanoenzyme presented in the coating alleviated OS and O_(2) deficiency at the injury site by catalyzing the decomposition of abundant endogenous H_(2)O_(2) around the modified Ti implants into O_(2).In addition,Sr ions were released from the surface of the implant at a certain rate in a body-fluid environment,further promoting the adhesion,growth,and osteogenic differentiation of mesenchymal stem cells.More importantly,a Sprague Dawley rat femur model demonstrated that the modified Ti implant showed significant potential to accelerate bone tissue reconstruction in vivo.In sum-mary,the present system provides a new idea for the treatment of bone injury and the development of new orthopedic implants.

A novel biomimetic trabecular bone metal plate for bone repair and osseointegration

Fracture is one of the most common traumatic diseases in clinical practice,and metal plates have always been the first choice for fracture treatment because of their high strength.However,the bone plates have high elastic modulus and do not match the biomechanics of human bone,which adversely affects callus formation and fracture healing.Moreover,the complex microenvironment in the human body can induce corrosion of metallic materials and release toxic ions,which reduces the biocompatibility of the bone plate,and may necessitate surgical removal of the implant.In this study,tantalum(Ta)was deposited on porous silicon carbide(SiC)scaffolds by chemical vapor deposition technology to prepare a novel porous tantalum(pTa)trabecular bone metal plate.The function of the novel bone plate was evaluated by implantation in an animal fracture model.The results showed that the novel bone plate was effective in fracture fixation,without breakage.Both X-ray and microcomputed tomography analysis showed indirect healing by both pTa trabecular bone metal plates and titanium(Ti)plates;however,elastic fixation and obvious callus formation were observed after fixation with pTa trabecular bone metal plates,indicating better bone repair.Histology showed that pTa promoted the formation of new bone and integrated well with the host bone.Therefore,this novel pTa trabecular bone metal plate has good prospects for application in treating fractures.

A biomimetic gradient porous cage with a micro-structure for enhancing mechanical properties and accelerating osseointegration in spinal fusion

Objectives:Spinal fusion is a widely employed treatment of patients with degenerative disc disease,in which a cage is used to replace the disc for spinal fusion.But it often fails for insufficient mechanical strength and poor osseointegration.Here,we designed a polyether-ether-ketone(PEEK)/tantalum(Ta)composite cage with a biomimetic gradient porous micro-structure,simultaneously enhancing mechanical properties and accelerating osseointegration in spinal fusion.Materials and methods:In the study,based on the mechanical performances of PEEK and osteogenic potential of Ta,and the three-dimensional(3D)structures of cuttlebone and vertebra,the cages were respectively 3D printed by pure PEEK,PEEK with 5 wt%Ta(PEEK/Ta-5),PEEK with 10 wt%Ta(PEEK/Ta-10)and PEEK with 15 wt%Ta(PEEK/Ta-15),then verifiedin vitroand in sheep cervical fusion model systematically.Results:Vertebral Gyroid structure PEEK/Ta-15 cage exhibited superior mechanical properties than Cuttlebone-like structure PEEK/Ta-15 cage,closer to the cervical vertebra.Furthermore,PEEK/Ta-15 cage with higher Ta microparticles in PEEK provided a biomimetic gradient porous micro-structure with higher surface energy,guiding cell biological behavior,promoting new bone penetration,and accelerating osseointegrationin vivo.Conclusion:In conclusion,the study designed a biomimetic gradient porous cage with a micro-structure for enhancing mechanical properties,accelerating osseointegration and forming an anatomical lock in the fusion segment through composites,mechanical efficiency,surface extension,and pores.

Two decades of continuous progresses and breakthroughs in the field of bioactive ceramics and glasses driven by CICECO-hub scientists

Over the past two decades, the CICECO-hub scientists have devoted substantial efforts to advancing bioactiveinorganic materials based on calcium phosphates and alkali-free bioactive glasses. A key focus has been thedeliberate incorporation of therapeutic ions like Mg, Sr, Zn, Mn, or Ga to enhance osteointegration and vascularization,confer antioxidant properties, and impart antimicrobial effects, marking significant contributions tothe field of biomaterials and bone tissue engineering. Such an approach is expected to circumvent the uncertaintiesposed by methods relying on growth factors, such as bone morphogenetic proteins, parathyroidhormone, and platelet-rich plasma, along with their associated high costs and potential adverse side effects. Thiscomprehensive overview of CICECO-hub’s significant contributions to the forefront inorganic biomaterials acrossall research aspects and dimensionalities (powders, granules, thin films, bulk materials, and porous structures),follows a unified approach rooted in a cohesive conceptual framework, including synthesis, characterization, andtesting protocols. Tangible outcomes [injectable cements, durable implant coatings, and bone graft substitutes(scaffolds) featuring customized porous architectures for implant fixation, osteointegration, accelerated boneregeneration in critical-sized bone defects] were achieved. The manuscript showcases specific biofunctionalexamples of successful biomedical applications and effective translations to the market of bone grafts foradvanced therapies.

3D-printed surface promoting osteogenic differentiation and angiogenetic factor expression of BMSCs on Ti6Al4V implants and early osseointegration in vivo

Three-dimensional-printed(3 D-P) titanium implants display many advantages, such as design flexibility,higher efficiency, the capability to easily construct complex or customized structures, etc., and is believed to potentially replace traditional implants. However, the biological performance of the 3 D-P titanium surface has not been investigated systematically. Herein, we analyzed the surface characteristics of 3 D-P Ti6 Al4 V implants and evaluated the biological responses of bone marrow derived mesenchymal stromal cells(BMSCs) to the 3 D-P surface in vitro. Moreover, after implantation into the rat femoral condyle for3 and 6 weeks, the osseointegration performance was evaluated. The results showed the 3 D-P Ti6 Al4 V implant presented distinct fluctuant macroscale rough surface and relatively better hydrophilicity which enhanced the adhesion, proliferation, osteogenic differentiation and angiogenetic factor expression of BMSCs. Moreover, the in vivo osseointegration performance was also better than that of the control group at the early stage. The present study suggested the 3 D-P titanium alloy is a promising candidate to be used as implant material.

Strategies for creating living, additively manufactured, open-cellular metal and alloy implants by promoting osseointegration,osteoinduction and vascularization: An overview

Additive manufacturing of porous, open-cellular metal or alloy implants, fabricated by laser or electron beam melting of a powder bed, is briefly reviewed in relation to optimizing biomechanical compatibility by assuring elastic(Young's) modulus matching of proximate bone, along with corresponding pore sizes assuring osseointegration and vasculature development and migration. In addition, associated, requisite compressive and fatigue strengths for such implants are described. Strategies for optimizing osteoblast(bone cell) development and osteoinduction as well as vascularization of tissue in 3 D scaffolds and tissue engineering constructs for bone repair are reviewed in relation to the biology of osteogenesis and neovascularization in bone, and the role of associated growth factors, bone morphogenic proteins, signaling molecules and the like. Prospects for infusing hydrogel/collagen matrices containing these cellular and protein components or surgically extracted intramedullary(bone marrow) concentrate/aspirate containing these biological and cell components into porous implants are discussed, as strategies for creating living implants, which over the long term would act as metal or alloy scaffolds.

Fabrication of open-cellular(porous) titanium alloy implants: osseointegration, vascularization and preliminary human trials

In this study we describe the fabrication of a variety of open-cellular titanium alloy（Ti-6 Al-4 V） implants,both reticular mesh and foam structures, using electron beam melting（EBM）. These structures allow for the elimination of stress shielding by adjusting the porosity（or density） to produce an elastic modulus（or stiffness） to match that of both soft（trabecular） and hard（cortical） bone, as well as allowing for bone cell ingrowth, increased cell density, and all-matrix interactions; the latter involving the interplay between bone morphogenetic protein（BMP-2） and osteoblast functions. The early formation and characterization of elementary vascular structures in an aqueous hydrogel matrix are illustrated.Preliminary results for both animal（sheep） and human trials for a number of EBM-fabricated, and often patient-specific Tialloy implants are also presented and summarized. The results, while preliminary, support the concept and development of successful, porous, engineered ＂living＂ implants.