• dentifrices
• acidic
• prosthesis
• elements
• solution
• inflammation

• Titanium/chemistry
• Dental Implants
• Macrophages/metabolism
• Macrophages/drug effects
• Fluorides/chemistry
• Surface Properties
• Microscopy, Electron, Scanning
• Particle Size
• Hydrogen-Ion Concentration
• Interleukin-1beta
• Animals

• ALTR
• ALVAL
• CoCrMo
• adverse local tissue reaction
• corrosion
• metal release

• MRI
• Morris water maze
• PIXE
• behavioral tests
• cobalt
• electron microscopy
• minocycline
• neurodegeneration
• open field test

• Animals
• Cobalt/toxicity
• Brain/drug effects
• Brain/pathology
• Brain/metabolism
• Mice
• Mice, Inbred C57BL
• Male
• Oxidative Stress/drug effects
• Blood-Brain Barrier/drug effects
• Blood-Brain Barrier/pathology
• Blood-Brain Barrier/metabolism
• Minocycline/pharmacology
• Mitochondria/drug effects
• Mitochondria/metabolism
• Behavior, Animal/drug effects
• Magnetic Resonance Imaging

• 2509/21 Israel Science Foundation
• 1 CSRD VA
• 1 CSRD VA

• corrosion resistance
• denture base materials
• hardness
• powder metallurgy
• simulated artificial saliva
• titanium–molybdenum biomaterials
• wear rate

• King Salman Center for Disability Research

• PAI-1 (plasminogen activator inhibitor-1)
• TNF-α (tumor necrosis factor-alpha)
• cytokine interactions
• inflammation biomarkers
• interleukin (IL)
• pain management
• postoperative inflammation
• surgical outcomes
• therapeutic targets

• USP788
• biomaterials
• implant
• implant debris
• orthopedic
• particle

• Arthroplasty, Replacement, Hip/methods
• Titanium
• Hip Prosthesis
• Durapatite
• Alloys

• BioEngineering Solutions, Inc (Oak Park, IL)
• Crown Family Chair in Orthopedics (Rush University Medical Center)

• bone metabolism
• osseointegration
• peri‐implant disease
• smoking
• titanium particles

• Humans
• Dental Implants/adverse effects
• Osseointegration/physiology
• Alveolar Bone Loss/metabolism
• Alveolar Bone Loss/etiology
• Peri-Implantitis/metabolism
• Peri-Implantitis/etiology
• Dental Implantation, Endosseous
• Titanium
• Surface Properties
• Smoking/adverse effects

• environmental health
• human health
• microplastics
• ocean health
• plastic additives
• plastic life cycle

• United States
• Child
• Animals
• Humans
• Male
• Female
• Child, Preschool
• Plastics/toxicity
• Plastics/chemistry
• Ecosystem
• Monaco
• Microplastics
• Persistent Organic Pollutants
• Greenhouse Gases
• Cardiovascular Diseases
• Endocrine Disruptors/toxicity
• Flame Retardants
• Lung Neoplasms
• Coal
• Pulmonary Disease, Chronic Obstructive

• P01 ES028938 NIEHS NIH HHS
• Minderoo Foundation
• A modern philanthropic organization
• Centre Scientifique de Monaco
• Prince Albert II of Monaco Foundation

• arthroplasty
• cytokines
• implant
• osteolysis
• wear debris

Release of metallic wear particles from hip replacement implants is closely associated with aseptic loosening that affects the functionality and survivorship of the prostheses. Chromium oxide nanoparticles (CrNPs) are the dominant form of the wear particles found in the periprosthetic tissues. Whether CrNPs play a role in the clinically observed particle-induced osteolysis, tissue inflammatory reactions and functional activities of human mesenchymal stem cells (MSCs) remain unknown.

A tibia-defect rat model, cytotoxicity assays and flow cytometry were applied to study the effect of CrNPs on MSCs survival and macrophage inflammatory response. Also, oscillatory fluid flow stimulation was used to analyse the osteogenic differentiation of MSCs while treated by CrNPs. In addition, the influence of CrNPs on MSC biomechanical properties was determined via atomic force microscope (AFM) and fluorescence microscopy.

It was found that implantation of CrNPs significantly decreased bone formation in vivo. CrNPs had no obvious effects on inflammatory cytokines release of U937 macrophages. Additionally, CrNPs did not interfere with MSCs osteogenic differentiation under static culture. However, the upregulated osteogenic differentiation of MSCs due to fluid flow stimulation was reduced by CrNPs in a dose-dependent manner. Moreover, osteogenic gene expression of OPN, Cox2 and Rnux2 after mechanical stimulation was also decreased by CrNPs treatments. Furthermore, cell elasticity and adhesion force of MSCs were affected by CrNPs over 3 days of exposure. We further verified that these effects of CrNPs could be associated with its interruption on cell mechanical properties.

The results demonstrated that CrNPs impaired cellular response to mechanical stimulus and osteogenesis without noticeable effects on the survival of the human MSCs.

• chromium nanoparticle
• cytoskeleton
• human mesenchymal stem cells
• mechanical stimulation
• osteogenesis

• Locking Mechanism
• Metallosis
• Osteolysis
• Primary Total Knee Arthroplasty

• Alloys/chemistry
• Biocompatible Materials
• Cell Line
• Cell Proliferation
• Cell Survival
• Dental Implants
• Humans
• Materials Testing
• Osteoblasts
• Osteogenesis
• Titanium/chemistry
• Zirconium/chemistry

• Natural Science Foundation of Hunan Province
• Young Scientists Fund

• Bearings
• Dislocation
• Hip capsule
• Total hip replacement

• 50%Nb-xTi-Zr alloy
• biocompatibility
• dental pure titanium
• elastic modulus
• osteogenic activity

• Nb-Ti-Zr
• biocompatibility
• cell proliferation
• elastic modulus
• powder metallurgy

The toxicity of released metallic particles generated in metal-on-metal (MoM) total hip arthroplasty (THA) using cobalt chromium (CoCr) has raised concerns regarding their safety amongst both surgeons and the public. Soft tissue changes such as pseudotumours and metallosis have been widely observed following the use of these implants, which release metallic by-products due to both wear and corrosion. Although activated fibroblasts, the dominant cell type in soft tissues, have been linked to many diseases, the role of synovial fibroblasts in the adverse reactions caused by CoCr implants remains unknown. To investigate the influence of implants manufactured from CoCr, the periprosthetic synovial tissues and synovial fibroblasts from patients with failed MoM THA, undergoing a revision operation, were analysed and compared with samples from patients undergoing a primary hip replacement, in order to elucidate histological and cellular changes.

Periprosthetic tissue from patients with MoM implants was characterized by marked fibrotic changes, notably an increase in collagen content from less than 20% to 45–55%, an increase in α-smooth muscle actin positive cells from 4 to 9% as well as immune cells infiltration. Primary cell culture results demonstrated that MoM synovial fibroblasts have a decreased apoptosis rate from 14 to 6% compared to control synovial fibroblasts. In addition, synovial fibroblasts from MoM patients retained higher contractility and increased responsiveness to chemotaxis in matrix contraction. Their mechanical properties at a single cell level increased as observed by a 60% increase in contraction force and higher cell stiffness (3.3 kPa in MoM vs 2.18 kPa in control), as measured by traction force microscopy and atomic force microscopy. Further, fibroblasts from MoM patients promoted immune cell invasion by secreting monocyte chemoattractant protein 1 (MCP-1, CCL2) and induced monocyte differentiation, which could also be associated with excess accumulation of synovial macrophages.

Synovial fibroblasts exposed in vivo to MoM THA implants that release CoCr wear debris displayed dramatic phenotypic alteration and functional changes. These findings unravelled an unexpected effect of the CoCr alloy and demonstrated an important role of synovial fibroblasts in the undesired tissue reactions caused by MoM THAs.

• Cobalt chromium debris
• Fibrosis
• Inflammation
• Synovial fibroblast

When presented with an adverse stimulus, organisms evoke an immediate, pre-programmed, non-specific innate immune response. The purpose of this reaction is to maintain the organism's biological integrity and function, mitigate or eradicate the injurious source, and re-establish tissue homeostasis. The initial stage of this protective reaction is acute inflammation, which normally reduces or terminates the offending stimulus. As the inflammatory reaction recedes, the stage of tissue repair and regeneration follows. If the above sequence of events is perturbed, reconstitution of normal biological form and function will not be achieved. Dysregulation of these activities may result in incomplete healing, fibrosis, or chronic inflammation. Our laboratory has studied the reaction to wear particles from joint replacements as a paradigm for understanding the biological pathways of acute and chronic inflammation, and potential translational treatments to reconstitute lost bone. As inflammation is the cornerstone for healing in all anatomical locations, the concepts developed have relevance to tissue engineering and regenerative medicine in all organ systems. To accomplish our goal, we developed novel in vitro and in vivo models (including the murine femoral continuous intramedullary particle infusion model), translational strategies including modulation of macrophage chemotaxis and polarization, and methods to interfere with key transcription factors NFκB and MyD88. We purposefully modified MSCs to facilitate bone healing in inflammatory scenarios: by preconditioning the MSCs, and by genetically modifying MSCs to first sense NFκB activation and then overexpress the anti-inflammatory pro-regenerative cytokine IL-4. These advancements provide significant translational opportunities to enhance healing in bone and other organs.

• bone healing
• bone repair
• inflammation
• osteogenesis
• wear particle disease

• Alloys
• biofilms
• dental implant
• proteomics
• salivary pellicle
• titanium

• Adsorption
• Alloys/chemistry
• Bacterial Adhesion
• Biocompatible Materials/chemistry
• Dental Pellicle/chemistry
• Niobium/chemistry
• Proteome/analysis
• Proteomics
• Salivary Proteins and Peptides/analysis
• Titanium/chemistry
• Zirconium/chemistry

Currently, there is a dearth of information regarding the degree of particle shedding from breast implants (BIs) and what are the general biological consequences of BI debris. Thus, it is unclear to what degree BI debris compromises the long-term biological performance of BIs. For orthopedic implants, it is well established that the severity of biological reactivity to implant debris governs long-term clinical performance. Orthopedic implant particulate debris is generally in the range of 0.01 to 100 μm in diameter. Implant debris-induced bioreactivity/inflammation is mostly a peri-implant phenomenon caused by local innate immune cells (eg, macrophages) that produce proinflammatory cytokines such as tumor necrosis factor-α, interleukin-1β, interleukin-6, and prostaglandin 2 (PGE2). In orthopedics, there have been few systemic concerns associated with polymeric implant debris (like silicone) other than documented dissemination to remote organs (eg, liver, spleen, etc.) with no known associated pathogenicity. This is not true of metal implant debris where normal (well-functioning) implants can induce systemic reactions such as delayed type hypersensitivity. Diagnostic analysis of orthopedic tissues has focused on innate (macrophage mediated) and adaptive (lymphocyte-mediated hypersensitivity) immune responses. Orthopedic implant debris-associated lymphocyte cancers have not been reported in over 40 years of orthopedic literature. Adaptive immune responses such as hypersensitivity reactions to orthopedic implant debris have been dominated by certain implant types that produce specific kinds of debris (eg, metal-on-metal total joint prostheses). Orthopedic hypersensitivity responses and atypical BI bioreactivity such as BI-associated anaplastic large cell lymphoma share crossover markers for diagnosis. Differentiating normal innate immune reactivity to particles from anaplastic large cell lymphoma reactions from delayed type hypersensitivity reactions to BI-associated implant debris remains unclear but vital to patients and surgeons.

Focal bone resorption (osteolysis) induced by wear particles contributes to long-term orthopedic joint failure. However, the impact of focal osteolysis on remote skeletal sites has received less attention. The goal of this study was to determine the effects of polyethylene particles placed over calvaria on representative axial and appendicular skeletal sites in female mice. Because recent work has identified housing temperature as an important biological variable in mice, response to particle treatment was measured in animals housed at room (22 °C) and thermoneutral (32 °C) temperature. Osteolysis was evident in skeletal tissue adjacent to particle insertion. In addition, cancellous bone loss was observed in distal femur metaphysis. The bone loss was associated with lower osteoblast-lined perimeter and lower mineralizing perimeter in distal femur, lower osteocalcin gene expression in tibia, and lower serum osteocalcin, suggesting the response was due, at least in part, to reduced bone formation. Mild cold stress induced by sub-thermoneutral housing resulted in cancellous bone loss in distal femur and lumbar vertebra but did not influence skeletal response to particles. In summary, the results indicate that focal inflammation induced by polyethylene particles has the potential to result in systemic bone loss. This is significant because bone loss is a risk factor for fracture.

•

Wear particles contribute to orthopedic joint failure by promoting focal inflammation- mediated osteolysis.

• Bone formation
• Bone resorption
• Osteolysis
• Osteoporosis

It is now well established that intra-articular deposition of endogenous particulates, such as osteoarthritis-associated basic calcium phosphate crystals, gout-associated monosodium urate crystals, and calcium deposition disease-associated calcium pyrophosphate crystals, contributes to joint destruction through the production of cartilage-degrading enzymes and pro-inflammatory cytokines. Furthermore, exogenous wear-debris particles, generated from prosthetic implants, drive periprosthetic osteolysis which impacts on the longevity of total joint replacements. Over the last few years, significant insight has been gained into the mechanisms through which these particulates exert their effects. Not only has this increased our understanding of the pathological processes associated with crystal deposition but it has also led to the identification of a number of therapeutic targets to treat particulate-associated disease. In this review, we discuss recent developments regarding the cellular events triggered by joint-associated particulates, as well as future directions in therapy for particulate-related arthropathies.

• calcium deposition disease
• gout
• joint inflammation
• osteoarthritis
• particulates

Histological assessments of synovial tissues from patients with failed CoCr alloy hip prostheses demonstrate extensive infiltration and accumulation of macrophages, often loaded with large quantities of particulate debris. The resulting adverse reaction to metal debris (ARMD) frequently leads to early joint revision. Inflammatory response starts with the recruitment of immune cells and requires the egress of macrophages from the inflamed site for resolution of the reaction. Metal ions (Co²⁺ and Cr³⁺) have been shown to stimulate the migration of T lymphocytes but their effects on macrophages motility are still poorly understood. To elucidate this, we studied in vitro and in vivo macrophage migration during exposure to cobalt and chromium ions and nanoparticles. We found that cobalt but not chromium significantly reduces macrophage motility. This involves increase in cell spreading, formation of intracellular podosome-type adhesion structures and enhanced cell adhesion to the extracellular matrix (ECM). The formation of podosomes was also associated with the production and activation of matrix metalloproteinase-9 (MMP9) and enhanced ECM degradation. We showed that these were driven by the down-regulation of RhoA signalling through the generation of reactive oxygen species (ROS). These novel findings reveal the key mechanisms driving the wear/corrosion metallic byproducts-induced inflammatory response at non-toxic concentrations.

Adverse tissue responses to metal wear and corrosion products from CoCr alloy implants remain a great challenge to surgeons and patients. Macrophages are the key regulators of these adverse responses to the ions and debris generated. We demonstrated that cobalt, rather than chromium, causes macrophage retention by restructuring the cytoskeleton and inhibiting cell migration via ROS production that affects Rho Family GTPase. This distinctive effect of cobalt on macrophage behaviour can help us understand the pathogenesis of ARMD and the cellular response to cobalt based alloys, which provide useful information for future implant design and biocompatibility testing.

• Cobalt chromium
• Macrophage
• Nanoparticles
• ROS
• Wear debris

• Animals
• Cobalt/adverse effects
• Cobalt/chemistry
• Cobalt/pharmacology
• Foreign-Body Reaction/chemically induced
• Foreign-Body Reaction/metabolism
• Foreign-Body Reaction/pathology
• Gene Expression Regulation/drug effects
• Humans
• Macrophages/metabolism
• Macrophages/pathology
• Metal Nanoparticles/adverse effects
• Metal Nanoparticles/chemistry
• Mice
• Reactive Oxygen Species/metabolism
• Signal Transduction/drug effects
• U937 Cells
• rho GTP-Binding Proteins/biosynthesis
• rhoA GTP-Binding Protein/biosynthesis

• FS/15/74/31669 British Heart Foundation

T-cells, second only to macrophages, are often considered as the potential cells involved in debris-related failure of arthroplasty. Here, we assessed the effects of particulate wear debris on T-cells and inflammatory reactions. Blood samples from 25 donors were incubated with polyether-ether-ketone (PEEK) and cobalt-chromium-molybdenum (CoCrMo) particles generated by custom cryo-milling and pulverization. The T-cell phenotypes were assessed using immunostaining and flow cytometry. For the in vivo study, 0.1 mL of each particle suspension (approximately 1.0 × 10⁸ wear particles) was injected into murine knee joints; the synovium and spleen were collected one week after the operation for histological examination and immunofluorescence staining. The T-cell responses observed included low-level activation of Th1, Th2, Th17, and CD8+ pathways after 72 h of co-culture of the particles with peripheral blood mononuclear cells. Obvious CD8+ T-cell responses were observed in local synovium and peripheral spleen, with higher inflammatory cytokine expression in the CoCrMo group. Relatively minor cytotoxic and immunological reactions were observed in vitro, with PEEK and CoCrMo particle-induced immune responses being primarily mediated by CD8+ T-cells, rather than CD4+ T-cells, in vivo. Overall, PEEK wear particles induced fewer inflammatory reactions than CoCrMo particles. This study verified that PEEK was suitable as a potential alternative for metals in total knee replacements in terms of the immunological reaction to PEEK particles, and shed light on the effects of wear particles from polymer and metal-based implants on immune responses.

• T-cell response
• cobalt-chromium-molybdenum
• joint arthroplasty
• polyether-ether-ketone
• wear particles

Recently, high failure rates of metal-on-metal (MOM) hip implants have raised concerns of cobalt toxicity. Adverse reactions occur to cobalt nanoparticles (CoNPs) and cobalt ions (Co²⁺) during wear of MOM hip implants, but the toxic mechanism is not clear.

To evaluate the protective effect of zinc ions (Zn²⁺), Balb/3T3 mouse fibroblast cells were pretreated with 50 μM Zn²⁺ for four hours. The cells were then exposed to different concentrations of CoNPs and Co²⁺ for four hours, 24 hours and 48 hours. The cell viabilities, reactive oxygen species (ROS) levels, and inflammatory cytokines were measured.

CoNPs and Co²⁺ can induce the increase of ROS and inflammatory cytokines, such as tumour necrosis factor α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6). However, Zn pretreatment can significantly prevent cytotoxicity induced by CoNPs and Co²⁺, decrease ROS production, and decrease levels of inflammatory cytokines in Balb/3T3 mouse fibroblast cells.

These results suggest that Zn pretreatment can provide protection against inflammation and cytotoxicity induced by CoNPs and Co²⁺ in Balb/3T3 cells.

Cite this article: Y. Liu, H. Zhu, H. Hong, W. Wang, F. Liu. Can zinc protect cells from the cytotoxic effects of cobalt ions and nanoparticles derived from metal-on-metal joint arthroplasties? Bone Joint Res 2017;6:649–655. DOI: 10.1302/2046-3758.612.BJR-2016-0137.R2.

• Cobalt cytotoxicity
• Cobalt ions
• Cobalt nanoparticles
• Protective effects
• Zinc

Millions of total joint replacements are performed annually worldwide, and the number is increasing every year. The overall proportion of patients achieving a successful outcome is about 80–90% in a 10–20-years time horizon postoperatively, periprosthetic osteolysis (PPOL) and aseptic loosening (AL) being the most frequent reasons for knee and hip implant failure and reoperations. The chemokine system (chemokine receptors and chemokines) is crucially involved in the inflammatory and osteolytic processes leading to PPOL/AL. Thus, the modulation of the interactions within the chemokine system may influence the extent of PPOL. Indeed, recent studies in murine models reported that (i) blocking the CCR2–CCL2 or CXCR2–CXCL2 axis or (ii) activation of the CXCR4–CXCL12 axis attenuate the osteolysis of artificial joints. Importantly, chemokines, inhibitory mutant chemokines, antagonists of chemokine receptors, or neutralizing antibodies to the chemokine system attached to or incorporated into the implant surface may influence the tissue responses and mitigate PPOL, thus increasing prosthesis longevity. This review summarizes the current state of the art of the knowledge of the chemokine system in human PPOL/AL. Furthermore, the potential for attenuating cell trafficking to the bone–implant interface and influencing tissue responses through modulation of the chemokine system is delineated. Additionally, the prospects of using immunoregenerative biomaterials (including chemokines) for the prevention of failed implants are discussed. Finally, this review highlights the need for a more sophisticated understanding of implant debris-induced changes in the chemokine system to mitigate this response effectively.

• aseptic loosening
• chemokine receptors
• immunoregenerative implant
• osteolysis
• therapeutics
• tissue homeostasis
• wear particles

• Alloys
• Corrosion
• Dental implant
• Titanium
• Zirconium

• NF-κB
• SIRT1
• aseptic loosening
• inflammatory response
• metal nanoparticle

• Acetylation
• Aged, 80 and over
• Animals
• Arthroplasty, Replacement, Hip/adverse effects
• Cytokines/metabolism
• Female
• Humans
• Inflammation/chemically induced
• Inflammation/metabolism
• Macrophages/drug effects
• Macrophages/metabolism
• Male
• Metal Nanoparticles/toxicity
• Mice, Inbred C57BL
• Middle Aged
• NF-kappa B/metabolism
• Osteolysis/metabolism
• Prostheses and Implants/adverse effects
• Prosthesis Failure
• Resveratrol
• Sirtuin 1/genetics
• Sirtuin 1/metabolism
• Stilbenes/pharmacology

• chemokines
• lymphocytes
• macrophages
• metal ions
• migration

• CXC
• allergy
• chemokines
• implant debris
• inflammasome
• orthopedics

• R01 AR060782 NIAMS NIH HHS

• alternative in vitro model
• macrophages
• periprosthetic osteolysis
• spontaneous osteoclastogenesis
• ultra-high molecular weight polyethylene

Wear particle-induced osteolysis is the leading cause of aseptic loosening, which is the most common reason for THA (total hip arthroplasty) failure and revision surgery. Although existing studies suggest that osteoblast apoptosis induced by wear debris is involved in aseptic loosening, the underlying mechanism linking wear particles to osteoblast apoptosis remains almost totally unknown. In the present study, we investigated the effect of autophagy on osteoblast apoptosis induced by CoCrMo metal particles (CoPs) in vitro and in a calvarial resorption animal model. Our study demonstrated that CoPs stimulated autophagy in osteoblasts and PIO (particle-induced osteolysis) animal models. Both autophagy inhibitor 3-MA (3-methyladenine) and siRNA of Atg5 could dramatically reduce CoPs-induced apoptosis in osteoblasts. Further, inhibition of autophagy with 3-MA ameliorated the severity of osteolysis in PIO animal models. Moreover, 3-MA also prevented osteoblast apoptosis in an antiautophagic way when tested in PIO model. Collectively, these results suggest that autophagy plays a key role in CoPs-induced osteolysis and that targeting autophagy-related pathways may represent a potential therapeutic approach for treating particle-induced peri-implant osteolysis.

• aseptic loosening
• autophagy
• osteoblasts
• osteolysis
• wear particles

• biological response
• biomaterials
• foreign body response
• inflammation
• orthopaedic implants

• biological response
• biomaterials
• foreign body response
• inflammation
• orthopedic implants

• Animals
• Calcium Compounds/chemistry
• Calcium Compounds/toxicity
• Cell Line
• Cell Survival/drug effects
• Cytokines/genetics
• Cytokines/metabolism
• Enzyme-Linked Immunosorbent Assay
• Gene Expression Regulation/drug effects
• Inflammation/chemically induced
• Inflammation/metabolism
• Macrophages/drug effects
• Materials Testing
• Mice
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Silicates/chemistry
• Silicates/toxicity
• Tissue Scaffolds

• Aseptic loosening
• Osteocyte
• Osteocytic osteolysis
• Periprosthetic
• Polyethylene
• UHMWPE