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A total knee arthroplasty system offers more distal femoral implant anterior-posterior (AP) sizes than its predecessor. The purpose of this study is to investigate the impact of increased size availability on an implant system's ability to reproduce the AP dimension of the native distal femur. We measured 200 cadaveric femora with the AP-sizing guides of Zimmer (Warsaw, IN) NexGen (8 sizes) and Zimmer Persona (12 sizes) total knee arthroplasty systems. We defined "size deviation" as the difference in the AP dimension between the anatomic size of the native femur and the closest implant size. We defined satisfactory reproduction of distal femoral dimensions as

The most important factor contributing to short-term and long-term success of cementless total joint arthroplasties is osseointegration. Osseointegration leads to a direct structural and functional connection between living bone and the surface of an implant. Surface contaminants may remain on orthopaedic implants after sterilization procedures and impair osseointegration. For example, specific lots of hip replacement Sulzer Inter-OP(TM) acetabular shells that were associated with impaired osseointegration and early failure rates were found to be contaminated with both bacterial debris and machine oil residues. However, the effect of machine oil on implant integration is unknown. Therefore, the goal of this study was to determine if machine oil inhibits the osseointegration of orthopaedic implants. To test this hypothesis in vivo we used our murine model of osseointegration where titanium alloy implants are implanted into a unicortical pilot hole in the mid-diaphysis of the femur. We found that machine oil inhibited bone-to-implant contact and biomechanical pullout measures. Machine oil on titanium alloy discs inhibited early stages of MC3T3-E1 osteogenesis in vitro such as attachment and spreading. Inhibition of osteoblast attachment and spreading occurred in both areas with and without detectable oil. Osteoblast growth was in turn inhibited on discs with machine oil due to both a decrease in proliferation and an increase in cell death. Later stages of osteogenic differentiation and mineralization on titanium alloy discs were also inhibited. Thus, machine oil can inhibit osseointegration through cell autonomous effects on osteoblast cells. These results support routine testing by manufacturers of machine oil residues on orthopaedic implants.

The study of the etiology of osteoarthritis (OA) of the hip has developed into a dynamic field over the past 50 years. Epidemiological, genetic, anatomical, and biological research indicates that hip osteoarthritis appears to be a distinct entity in comparison to arthritis that affects other joints. Significant racial and ethnic differences exist in the prevalence of hip OA. Several gene single nucleotide polymorphisms (SNPs) have been discovered that are associated with an increased risk for the development of hip OA. The ethnic distribution of these SNPs also supports the differences seen in hip OA prevalence. The notion of hip OA as a “primary” disease has been challenged by the continued development of the theory of femoroacetabular impingement (FAI). This theory posits that hip OA develops secondary to subtle anatomical differences compared to “normal” hips. The identification and surgical treatment of these differences may postpone or possibly prevent hip OA development. Advances in the understanding of important signaling pathways in OA progression, such as the Wnt and TGF-β pathways, provide potential targets for new therapeutic agents.

Hip resurfacing is an alternative to total hip arthroplasty.We aimed to compare an experienced hip surgeon's initial clinical results of hip resurfacing with a new cementless total hip arthroplasty (THA).The first 55 consecutive hip resurfacing arthroplasties were compared to 100 consecutive cementless THAs using a cylindrical tapered femoral stem. The learning curve between the two procedures was compared utilizing the incidence of reoperation, complications, Harris Hip Scores (HHS), and implant survivorship.The reoperation rate was significantly higher (p = 0.019) for hip resurfacing (14.5%) versus THA (4%). The overall complication rate between the two groups was not significantly different (p = 0.398). Preoperative HHS were similar between the two groups (p = 0.2). The final mean HHS was similar in both the resurfacing and THA groups (96 vs. 98.3, respectively, p 0.65). Kaplan-Meier survival analysis with an endpoint of reoperation suggests complications occurred earlier in the resurfacing group versus the THA group (log-rank test, p = 0.007).In comparison to our initial experience with a cementless THA stem, operative complications occur earlier and more often after hip resurfacing during the learning period. The clinical outcomes in both groups however are similar at 5 year follow-up.

Tissue engineering is a possible method for long-term repair of cartilage lesions, but current tissue-engineered cartilage constructs have inferior mechanical properties compared to native cartilage. This problem may be due to the lack of an oriented structure in the constructs at the microscale that is present in the native tissue. In this study, we utilize contact guidance to develop constructs with microscale architecture for improved chondrogenesis and function. Stable channels of varying microscale dimensions were formed in collagen-based and polydimethylsiloxane membranes via a combination of microfabrication and soft-lithography. Human mesenchymal stem cells (MSCs) were selectively seeded in these channels. The chondrogenic potential of MSCs seeded in these channels was investigated by culturing them for 3 weeks under differentiating conditions, and then evaluating the subsequent synthesized tissue for mechanical function and by type II collagen immunohistochemistry. We demonstrate selective seeding of viable MSCs within the channels. MSC aligned and produced mature collagen fibrils along the length of the channel in smaller linear channels of widths 25-100 μm compared to larger linear channels of widths 500-1000 μm. Further, substrates with microchannels that led to cell alignment also led to superior mechanical properties compared to constructs with randomly seeded cells or selectively seeded cells in larger channels. The ultimate stress and modulus of elasticity of constructs with cells seeded in smaller channels increased by as much as fourfolds. We conclude that microscale guidance is useful to produce oriented cartilage structures with improved mechanical properties. These findings can be used to fabricate large clinically useful MSC-cartilage constructs with superior mechanical properties.

Femoroacetabular impingement has been proposed as a cause of early osteoarthritis, but it is not known how this develops over time or whether the shape of the proximal femur influences this risk.(1) Which areas of the acetabulum are worn more frequently by individuals with a cam deformity of the proximal femur? (2) Do observed acetabular wear patterns differ based on the etiology of the cam deformity? (3) Do wear patterns of individuals with a cam deformity differ based on an individual's age?We examined 645 corresponding femora and acetabuli from the Hamann-Todd Osteological Collection and determined the offset and alpha angle using photographs; 370 specimens met inclusion criteria and were examined for signs of wear and the locations of wear were recorded. Specimens were separated into eight subgroups based on age either younger than 40 years or older than 60 years, alpha angle greater or less than 55°, and degree of anterior head-neck offset. We compared the prevalence of wear between groups in each location.Individuals with abnormal geometry of the proximal femur demonstrated different wear patterns from individuals with normal geometry. There were few differences in wear patterns identified based on the etiology of the femoral deformity. Abnormal femoral geometry was associated with more frequent wear primarily at the anterosuperior acetabulum for individuals younger than 40 years of age and globally for individuals older than 60 years of age.Femoral geometry appears to influence the pattern of acetabular wear occurring over time.

Osseointegration is the process by which an orthopaedic implant makes direct bone-to-implant contact and is crucial for the long-term function of the implant. Surface contaminants, such as bacterial debris and manufacturing residues, may remain on orthopaedic implants after sterilization and impair osseointegration. For example, specific lots of implants that were associated with impaired osseointegration and high failure rates were discovered to have contaminants including bacterial debris. Therefore, the goals of this study were to determine if bacterial debris exists on sterile orthopaedic implants and if adherent bacterial debris inhibits the osseointegration of orthopaedic implants. We found that debris containing lipopolysaccharide (LPS) from Gram-negative bacteria exists on both sterile craniofacial implants and wrist implants. Levels of bacterial debris vary not only between different lots of implants but within an individual lot. Using our murine model of osseointegration, we found that ultrapure LPS adherent to the implants inhibited bone-to-implant contact and biomechanical pullout measures. Analysis of osseointegration in knock-out mice demonstrated that adherent LPS inhibited osseointegration by signaling through its primary receptor, Toll-like receptor 4, and not by signaling through Toll-like receptor 2. Ultrapure LPS adherent to titanium alloy discs had no detectable effect on early stages of MC3T3-E1 osteogenesis in vitro such as attachment, spreading or growth. However, later stages of osteogenic differentiation and mineralization were inhibited by adherent LPS. Thus, LPS may inhibit osseointegration in part through cell autonomous effects on osteoblasts. These results highlight bacterial debris as a type of surface contaminant that can impair the osseointegration of orthopaedic implants.

Knee stiffness or limited range of motion (ROM) after total knee arthroplasty (TKA) may compromise patient function. Patients with stiffness are usually managed with manipulation under anesthesia (MUA) to improve ROM. However, the final ROM obtained is multifactorial and may depend on factors such as comorbidities, implant type, or the timing of MUA.We asked whether diabetes mellitus, implant type, and the interval between TKA and MUA influenced post-MUA ROM.From a group of 2462 patients with 3224 TKAs performed between 1999 and 2007 we retrospectively reviewed 96 patients with 119 TKAs (4.3%) who underwent MUA. We determined the presence of diabetes mellitus, implant type, and the interval between TKA and MUA.The average increase in ROM after MUA was 34°. Patients with diabetes mellitus experienced lower final ROM after MUA (87.5° versus 100.3°) as did patients with cruciate-retaining (CR) prostheses versus posterior-stabilized (92.3° versus 101.6°). The interval between TKA and MUA inversely correlated with final ROM with a decrease after 75 days.Most patients experience improvements in ROM after MUA. Patients with diabetes mellitus or CR prostheses are at risk for lower final ROM after MUA. Manipulation within 75 days of TKA is associated with better ROM.

Surface contaminants, such as bacterial debris and manufacturing residues, may remain on orthopaedic implants after sterilization procedures and affect osseointegration. The goals of this study were to develop a murine model of osseointegration in order to determine whether removing surface contaminants enhances osseointegration. To develop the murine model, titanium alloy implants were implanted into a unicortical pilot hole in the mid-diaphysis of the femur and osseointegration was measured over a five week time course. Histology, backscatter scanning electron microscopy and x-ray energy dispersive spectroscopy showed areas of bone in intimate physical contact with the implant, confirming osseointegration. Histomorphometric quantification of bone-to-implant contact and peri-implant bone and biomechanical pullout quantification of ultimate force, stiffness and work to failure increased significantly over time, also demonstrating successful osseointegration. We also found that a rigorous cleaning procedure significantly enhances bone-to-implant contact and biomechanical pullout measures by two-fold compared with implants that were autoclaved, as recommended by the manufacturer. The most likely interpretation of these results is that surface contaminants inhibit osseointegration. The results of this study justify the need for the development of better detection and removal techniques for contaminants on orthopaedic implants and other medical devices.

The mechanisms of damage at the polyethylene post in 3 contemporary tibial insert designs were evaluated and compared with a historical standard (Insall-Burstein II; Zimmer, Warsaw, Ind). One hundred five gamma sterilized posterior-stabilized tibial inserts were revised after an average of 4.7 years (0.05-13.6 years). Retrievals were classified according to their designs: Insall-Burstein II (n = 28); PFC (Johnson & Johnson, Raynham, Mass; n = 30); NexGen (Zimmer; n = 32); and Scorpio (Stryker Orthopaedics, Mahwah, NJ; n = 15). Reasons for revision and patient details were available. Surface damage scoring and photogrammetry were performed on all the retrieved tibial inserts. Oxidation analysis was carried out for traceable historical, gamma air-sterilized and conventional, gamma inert-sterilized tibial inserts (n = 61) with the use of infrared spectroscopy. The posts for all 3 contemporary designs exhibited damage similar to the historical controls. Articular, post, and backside damage scores significantly increased with implantation time. Post damage was insensitive to design and patient factors but was exacerbated by oxidation. An association between damage at the post and articular surface was also confirmed. Logistic models suggested an interaction between post damage, backside surface damage, and implant loosening.

SummaryOsteoarthritis (OA) is the most common type of arthritis and a major cause of chronic musculoskeletal pain and functional disability. While both pharmacologic and non-pharmacologic modalities are recommended in the management of OA, when patients with hip or knee OA do not obtain adequate pain relief and/or functional improvement, joint replacement surgery or other surgical interventions should be considered. Total joint arthroplasties are reliable and cost-effective treatments for patients with significant OA of the hip and knee. Evidence from cohort and observational studies has confirmed substantial improvements in pain relief with cumulative revision rates at 10 years following total hip (THA) and total knee arthroplasties (TKA) at 7% and 10%, respectively. Joint replacements have been used in most every synovial joint, although results for joints other than hip and knee replacement have not been as successful. The evolution of new device designs and surgical techniques highlights the need to better understand the risk to benefit ratio for different joint replacements and to identify the appropriate methodology for evaluating the efficacy and optimal outcomes of these new devices, designed to treat OA joints.

Postoperative anterior knee pain can be challenging after primary total knee arthroplasty. Isolated patellar resurfacing may provide symptomatic improvement in those patients with an unresurfaced patella. Seventeen isolated patellar resurfacing procedures were performed. Patient outcomes were evaluated using the Knee Society clinical and roentgenographic evaluation systems. Continued symptomatology and overall patient satisfaction were also analyzed. No revisions have been necessary at 47 months of follow-up. Overall, Knee Society knee scores and knee function scores significantly improved. Eight patients (53%) are asymptomatic and were satisfied with the procedure, whereas 7 patients (47%) continue to have anterior knee pain and are unsatisfied. Isolated patellar resurfacing for anterior knee pain in total knee arthroplasty with an unresurfaced patella has a low morbidity and revision rate but may not provide patients with predictable symptomatic improvement.

Postthrombotic syndrome (PTS) is characterized by edema, venous ectasia, hyperpigmentation, varicose veins, venous ulceration, and pain with calf compression after deep venous thrombosis (DVT). We determined the incidence of PTS after DVT diagnosed on screening ultrasound in patients undergoing primary total knee arthroplasty (TKA) for osteoarthritis (OA). We retrospectively reviewed the records of 1406 patients who underwent primary TKA for osteoarthritis and compared the incidence of PTS in patients without and with DVT. All patients had postoperative screening ultrasound. From these 1406 patients we identified 66 (4.7%) who had DVT, 50 of whom had a minimum of 1 year followup (mean, 4.97 years; range, 1.00-7.53 years). PTS was diagnosed if any two of six signs were documented in the medical record. Three of 50 patients with DVT (6%) had signs consistent with PTS; two of these three had a DVT proximal to the soleal arch. Seven (8%) of 88 patients randomly chosen for primary TKA because of OA with similar mean age and gender, but without DVT, had signs of PTS. PTS does not seem to be a major sequela of DVT in patients undergoing primary TKA for OA.Level III, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.

Mobile-bearing total knee Arthroplasties (TKAs) were designed to increase conformity, decrease contact stresses, and decrease polyethylene damage. Our objective was to evaluate the performance of retrieved mobile-bearing TKAs with respect to wear damage of the polyethylene in a series of components obtained at revision surgery. Tibial component polyethylene superior and inferior surface damage and radiographic radiolucency analysis was conducted on 40 retrieved mobile-bearing TKAs. Higher levels of superior articulating surface damage were found to be associated with higher levels of inferior surface damage in this retrieval study. Greater levels of damage were present on both surfaces in components with greater radiographic radiolucency scores and mechanically loose components. The mobile-bearing TKA remains vulnerable to polyethylene wear damage at the superior surface and introduces an independent inferior surface also vulnerable to wear damage.

Bone loss that causes aseptic loosening of orthopedic implants is initiated by pro-inflammatory cytokines produced by macrophages in response to implant-derived wear particles. MAPK and NF-kappaB signaling pathways are activated by the particles; however, it is not clear which of the signaling pathways are important for the initial response to the wear particles and which are only involved at later steps in the process, such as osteoclast differentiation. Here, we show that the ERK1/2, p38, JNK, and NF-kappaB pathways are rapidly activated by the wear particles but that only the ERK1/2 and NF-kappaB pathways are required for the initial response to the wear particles, which include increases in TNFalpha promoter activity, TNFalpha mRNA expression, and secretion of TNFalpha protein. Moreover, ERK1/2 activation by wear particles is also required for increased expression of the transcription factor Egr-1 as well as Egr-1's ability to bind to and activate the TNFalpha promoter. These results, together with our previous studies of the PI3K/Akt pathway, demonstrate that wear particles coordinately activate multiple signaling pathways and multiple transcription factors to stimulate production of pro-inflammatory cytokines, such as TNFalpha. The current study also demonstrates that the signaling pathways are activated to a much greater extent by wear particles with adherent endotoxin than by "endotoxin-free" wear particles. These results, together with those demonstrating the requirement for ERK1/2/Egr-1 and NF-kappaB, show that activation of these signaling pathways is responsible for the ability of adherent endotoxin to potentiate cytokine production, osteoclast differentiation, and bone loss induced by wear particles.

There are a number of options available to manage the patella when revising a failed total knee arthroplasty. If the previous patellar component is well-fixed, undamaged, not worn, and compatible with the femoral revision component, then it can be retained. When a patellar component necessitates revision and is removed with adequate remaining patellar bone stock, an onlay-type all-polyethylene cemented implant can be used. Management of the patella with severe bony deficiency remains controversial. Treatment options for the severely deficient patella include the use of a cemented all-polyethylene biconvex patellar prosthesis, patellar bone grafting and augmentation, patellar resection arthroplasty (patelloplasty), performing a gull-wing osteotomy, patellectomy, or the use of newer technology such as a tantalum (trabecular metal) patellar prosthesis. Severe patellar bone deficiency is a challenging situation because restoration of the extensor mechanism, proper patellar tracking, and satisfactory anatomic relationships with the femoral and tibial components are critical for an optimal clinical outcome.Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.

Understanding the complex cellular and tissue mechanisms and interactions resulting in periprosthetic osteolysis requires a number of experimental approaches, each of which has its own set of advantages and limitations. In vitro models allow for the isolation of individual cell populations and have furthered our understanding of particle-cell interactions; however, they are limited because they do not mimic the complex tissue environment in which multiple cell interactions occur. In vivo animal models investigate the tissue interactions associated with periprosthetic osteolysis, but the choice of species and whether the implant system is subjected to mechanical load or to unloaded conditions are critical in assessing whether these models can be extrapolated to the clinical condition. Rigid analysis of retrieved tissue from clinical cases of osteolysis offers a different approach to studying the biologic process of osteolysis, but it is limited in that the tissue analyzed represents the end-stage of this process and, thus, may not reflect this process adequately.

Total joint arthroplasty is a highly successful procedure for end-stage lower extremity arthritis. Excellent pain relief and significantly improved function is usual after surgery when used for appropriate indications by highly skilled surgeons using contemporary designed components. Future improvement in design and materials to reduce wear will further enhance clinical outcomes and long-term implant survival.

Wear debris contributes to implant loosening after total joint arthroplasty, and few advances have been made in our ability to inhibit the biological response to wear particles. Bacterial endotoxins augment the effects of wear particles in vitro and in vivo. The cytokine, tumor necrosis factor-alpha (TNF-alpha), is produced by macrophages in response to bacterial endotoxins and wear particles, and it increases osteoclast activity resulting in bone resorption and implant loosening. The phosphoinositol-3-kinase (PI3K)-Akt intracellular signal transduction pathway contributes to cytokine production in response to soluble endotoxin. We investigated the role of the PI3K-Akt pathway in the production of TNF-alpha in response to wear particles with adherent endotoxin and so-called endotoxin-free wear particles.Cultured RAW264.7 murine macrophages were incubated with titanium particles with adherent endotoxin or with endotoxin-free titanium particles in the presence and absence of specific inhibitors of PI3K (LY294002) or Akt (SH-5). Akt activation was assessed with use of Western blot. TNF-alpha production was measured with use of enzyme-linked immunosorbent assay. Cytotoxicity was determined by measuring lactic dehydrogenase release.Titanium particles with adherent endotoxin increased Akt activation, whereas endotoxin-free titanium particles did not. The PI3K inhibitor reduced TNF-alpha production by 70% in response to titanium with adherent endotoxin without increasing cytotoxicity. Similarly, the Akt inhibitor reduced TNF-alpha production by 83% in response to titanium particles with adherent endotoxin without increasing cytotoxicity. High concentrations of endotoxin-free titanium particles resulted in a small delayed increase in TNF-alpha production that was completely blocked by the PI3K inhibitor.Inhibition of the PI3K-Akt pathway reduces macrophage TNF-alpha production in response to titanium particles with adherent endotoxin and endotoxin-free particles in vitro.

Bacterial endotoxin may contribute to aseptic loosening of orthopedic implants even in the absence of clinical or microbiological evidence of infection. One potential source of endotoxin during aseptic loosening is systemically circulating endotoxin, derived from intestinal flora, minor infections, or dental procedures, that may bind to wear particles. The current study demonstrates that systemically derived endotoxin accumulates when 'endotoxin-free' titanium and polyethylene particles are implanted on murine calvaria. Time-course experiments and experiments using germ-free mice rule out the possibility that the observed endotoxin accumulation may be due to bacterial contamination. In contrast, endotoxin is cleared from titanium particles that originally carry high amounts of adherent endotoxin. The mechanism of endotoxin clearance is not dependent on induction of a respiratory burst. Taken together, these results indicate that a balance between endotoxin accumulation and endotoxin clearance controls the steady-state level of endotoxin surrounding orthopedic wear particles implanted on murine calvaria. This balance may regulate the rate of osteolysis in the murine calvaria model as well as in patients with aseptic loosening.

Implant success is dependent in part on the interaction of the implant with the surrounding tissues. Porous tantalum implants (Trabecular Metal™, TM) have been shown to have excellent osseointegration. Machining this material to complex shapes with close tolerances is difficult because of its open structure and the ductile nature of metallic tantalum. Conventional machining results in occlusion of most of the surface porosity by the smearing of soft metal. This study compared TM samples finished by three processing techniques: conventional machining, electrical discharge machining, and nonmachined, “as-prepared.” The TM samples were studied in a rabbit distal femoral intramedullary osseointegration model and in cell culture. We assessed the effects of these machining methods at 4, 8, and 12 weeks after implant placement. The finishing technique had a profound effect on the physical presentation of the implant interface: conventional machining reduced surface porosity to 30% compared to bulk porosities in the 70% range. Bone ongrowth was similar in all groups, while bone ingrowth was significantly greater in the nonmachined samples. The resulting mechanical properties of the bone implant-interface were similar in all three groups, with only interface stiffness and interface shear modulus being significantly higher in the machined samples. © 2006 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2007

The unique arcade-like orientation of collagen fibers enables cartilage to bear mechanical loads. In this study continuous-length aligned collagen threads were woven to emulate the interdigitated arcade structure of the cartilage. The weaving pattern provided a macropore network within which micromass cell pellets were seeded to take advantage of mesenchymal condensation driven chondrogenesis. Compression tests showed that the baseline scaffold had a modulus of 0.83 ± 0.39 MPa at a porosity of 80%. The modulus of pellet seeded scaffolds increased by 60% to 1.33 ± 0.37 MPa after 28 days of culture, converging to the modulus of the native cartilage. The scaffolds displayed duress under displacement controlled low-cycle fatigue at 15% strain amplitude such that load reduction stabilized at 8% after 4500 cycles of loading. The woven structure demonstrated a substantial elastic recoil where 40% mechanical strain was close to completely recovered following unloading. A robust chondrogenesis was observed as evidenced by positive staining for GAGs and type II collagen and aggrecan. Dimethyl methylene blue and sircol assays showed GAGs and collagen productions to increase from 3.36 ± 1.24 and 31.46 ± 3.22 at day 3 to 56.61 ± 12.12 and 136.70 ± 12.29 μg/μg of DNA at day 28 of culture. This woven collagen scaffold holds a significant potential for cartilage regeneration with shorter in vitro culture periods due to functionally sufficient mechanical robustness at the baseline. In conclusion, the mimicry of cartilage’s arcade architecture resulted in substantial improvement of mechanical function while enabling one of the first pellet delivery platforms enabled by a macroporous network. Statement of significance Mesenchymal condensation is critical for driving chondrogenesis, making high density cell seeding a standard in cartilage tissue engineering. Efforts to date have utilized scaffold free delivery of MSCs in pellet form. This study developed a macroporous scaffold that is fabricated by weaving highly aligned collagen threads. The scaffold can deliver high density cell condensates while providing mechanical stiffness comparable to that of cartilage. The scaffold also mimicked the arcade-like orientation of collagen fibers in cartilage. A highly robust chondrogenesis was observed in this mesenchymal cell pellet delivery system. Baseline mechanical robustness of this scaffold system will enable delivery of cell pellets as early as three days.

Our research group developed an implant retrieval program to study in vivo degradation of polyethylene. We now have evidence to support our hypothesis that degradation of radiation-sterilized polyethylene occurs in the body for not only historical gamma air sterilized liners, but also for conventional gamma inert sterilized (ArCom) and annealed highly crosslinked polyethylene (Crossfire) liners as well. Our research has also led to the discovery that the most severe manifestations of in vivo oxidation typically occur in regions of the liner experiencing minimal wear, such as the rim of the component, where the body fluids (containing oxidizing species) have access to the polyethylene. Our data from historical, ArCom, and Crossfire retrievals all point to a similar scenario in which the femoral head limits the in vivo oxidation of polyethylene at the bearing surface. Consequently, provided rim impingement does not occur, and the polyethylene locking mechanisms remain relatively isolated from oxidizing fluid, in vivo oxidation does not seem to be clinically important in the first 10 years of implantation for conventional gamma sterilized polyethylene. We conclude that in vivo degradation should be included among the list of potential long-term failure modes for modular polyethylene components for total hip arthroplasty.

Posterior condylar offset (PCO) has important implications in total knee arthroplasty (TKA) function and design. In an osteological study of 1,058 femurs, we measured PCO using two separate techniques with a 3D digitizer. Measurements were standardized for the size of the femur. The medial PCO was greater than lateral PCO (32.6mm vs. 31.2mm, P0.0001). In 53% of individuals, the medial PCO differed between sides by more than 2mm. Age did not affect standardized medial or lateral PCO. Compared with African-Americans, Caucasians had a larger standardized medial (1.3mm vs. 1.2mm, P=0.006) and lateral (1.1mm vs. 1.0mm, P=0.004) PCOs. The standardized medial (1.2mm vs. 1.3mm, P=0.073), and lateral (1.1mm vs. 1.1mm, P=0.098), PCO did not differ between men and women, respectively.

Revision surgery on a failed patellar component can be difficult because of deficient residual bone that may compromise the functional outcome of the revision. We reviewed 20 knees in 20 patients in whom the residual patellar bone was less than 10 mm at the time of revision and used the Genesis Biconvex Patella implant to reconstruct the patella. The patients were followed up for an average of 34 months (range, 24-65 months), and were followed up clinically and radiographically by Knee Society criteria. Patellar revisions and complications were noted and standard radiographic studies to ascertain radiolucent lines and patella/patellar component thickness were evaluated. The Knee Society Scores improved from an average of 45 points to 89 points. Function scores improved from an average of 47 points to 65 points. None of the patients has required revision surgery and no patellar fractures have been seen. Radiographs showed complete lucencies at the cement-bone interface in two knees. The mean residual central patella bone thickness was 6.5 mm and the average postoperative composite thickness was 14.5 mm. The data indicate that the use of the Genesis Biconvex Patella implant is a satisfactory method of treating revision of the patella when there is major bone deficiency.Retrospective study, Level IV-1 (case study). See the Guidelines for Authors for a complete description of levels of evidence.

Summary Objective The natural repair of osteochondral defects can be enhanced with biocompatible, biodegradable materials that support the repair process. It is our hypothesis that hyaluronan-based scaffolds are superior to synthetic scaffolds because they provide biological cues. We tested this thesis by comparing two hyaluronan-based scaffolds [auto cross-linked polysaccharide polymer (ACP™) and HYAFF ® -11] to polyester-based scaffolds [poly(dl-lactic-co-glycolic acid) (PLGA) and poly(l-lactic acid) (PLLA)] with similar pore size, porosity and degradation times. Design Fifty-four rabbits received bilateral osteochondral defects. One defect received a hyaluronan-based scaffold and the contralateral defect received the corresponding polyester-based scaffold. Rabbits were euthanized 4, 12 and 20 weeks after surgery and the condyles dissected and processed for histology. Results Only ACP™-treated defects presented bone at the base of the defect at 4 weeks. At 12 weeks, only defects treated with rapidly dissolving implants (ACP™ and PLGA) presented bone reconstitution consistently, while bone was present in only one third of those treated with slowly dissolving scaffolds (HYAFF ® -11 and PLLA). After 20 weeks, the articular surface of PLGA-treated defects presented fibrillation more frequently than in ACP™-treated defects. The surface of defects treated with slowly dissolving scaffolds presented more cracks and fissures. Conclusions The degradation rate of the scaffolds is critical for the repair process. Slowly dissolving scaffolds sustain thicker cartilage at the surface but, it frequently presents cracks and discontinuities. These scaffolds also delay bone formation at the base of the defects. Hyaluronan-based scaffolds appear to allow faster cell infiltration leading to faster tissue formation. The degradation of ACP™ leads to rapid bone formation while the slow degradation of HYAFF ® -11 prolongs the presence of cartilage and delays endochondral bone formation.

Background: Ultra-high molecular weight polyethylene degrades during storage in air following gamma sterilization, but the extent of in vivo degradation remains unclear. The purpose of this study was to quantify the extent to which the mechanical properties and oxidation of conventional polyethylene acetabular liners treated with gamma sterilization in air change in vivo. Methods: Fourteen modular cementless acetabular liners were revised at an average of 10.3 years (range, 5.9 to 13.5 years) after implantation. All liners, which had been machined from GUR 415 resin, had been gamma-sterilized in air; the average shelf life was 0.3 year (range, 0.0 to 0.8 year). After removal, the components were expeditiously frozen to minimize ex vivo changes to the polyethylene prior to characterization. The average duration between freezing and testing was 0.6 year. Mechanical properties and oxidation were measured with use of the small-punch test and Fourier transform infrared spectroscopy, respectively, in the loaded and unloaded regions of the liners. Results: There was substantial regional variation in the mechanical properties and oxidation of the retrieved liners. The ultimate load was observed to vary by >90% near the surface. On the average, the rim and the unloaded bearing showed evidence of severe oxidation near the surface after long-term in vivo aging, but these trends were not typically observed on the loaded bearing surface or near the backside of the liners. Conclusions: The mechanical properties of polyethylene that has been gamma-sterilized in air may decrease substantially in vivo, depending on the location in the liner. The most severe oxidation was observed at the rim, suggesting that the femoral head inhibits access of oxygen-containing body fluids to the bearing surface. This is perhaps why in vivo oxidation has not been associated with clinical performance to date. Clinical Relevance: In vivo degradation of polyethylene liners that have been gamma-sterilized in air may be substantial, but the results of this study suggest that it is most frequently localized near the unworn surface regions of the liners. The performance of gamma-sterilized polyethylene liners should continue to be studied to determine whether the in vivo changes in properties have long-term clinical relevance.

Summary Objective Although available nonsurgical pharmacotherapies for treatment of osteoarthritis (OA) are considered to be solely symptom-modifying agents, recent advances have been made in the search for agents that may modify disease progression. Intra-articular hyaluronan (HA) therapy is one symptom-modifying approach that has been found to be safe and effective for reducing pain due to OA of the knee. Presented here is a review of the evidence that HAs may also modify the rate of OA disease progression in addition to providing symptomatic efficacy. Design A review of the literature based on a MEDLINE search through June 2004, using the terms HA, sodium hyaluronate, hyaluronic acid, hylan, hylan G-F 20, OA, disease modification, structure modifying and joint structure. Results Evidence for disease-modifying activity of HAs stems from 1) the complex biochemical effects of HAs in the synovium and extracellular matrix of the articular cartilage, including interactions between exogenously administered HA and articular cartilage, subchondral bone, matrix proteoglycans, and collagens; 2) the effects of HA administration in animal models of OA, including total or partial meniscectomy and anterior cruciate ligament transectomy; 3) results of clinical trials using one HA, Hyalgan ® (sodium hyaluronate, molecular weight 500–730kDa) that evaluated structural outcomes, such as joint-space width, chondrocyte density and vitality, and arthroscopic evaluation of chondropathy. Discussion Growing preclinical and clinical evidence supports the notion that, in addition to relieving the symptoms of OA, HAs also modify the structure of the diseased joint and the rate of OA disease progression, at least early in the evolution of the disease process.

Human mesenchymal stem cells (hMSCs) expanded with and without fibroblast growth factor (FGF) supplementation were compared with respect to their proliferation rate, ability to differentiate along the chondrogenic pathway in vitro, and their gene expression profiles. hMSCs expanded in FGF-supplemented medium were smaller and proliferated more rapidly than hMSCs expanded in control conditions. Chondrogenic cultures made with FGF-treated cells were larger and contain more proteoglycan than those made with control cells. Furthermore, aggregates of FGF-treated cells lacked the collagen type I-positive and collagen type II-negative outer layer characteristic of aggregates of control cells. A total of 358 unique transcripts were differentially expressed in FGF-treated hMSCs. Of these, 150 were upregulated and 208 downregulated. Seventeen percent of these genes affect proliferation. Known genes associated with cellular signaling functions comprised the largest percentage ( approximately 20%) of differentially expressed transcripts. Eighty percent of differentially expressed extracellular matrix-related genes were downregulated. The present findings that FGF-2 enhances proliferation and differentiation of hMSCs adds to a growing body of evidence that cytokines modulate the differentiation potential and, perhaps, the multipotentiality of adult stem cells. With the generation of gene expression profiles of FGF-treated and control cells we have taken the first steps in the elucidation of the molecular mechanism(s) behind these phenomena.

The long term survival of the Miller-Galante I cementless total knee arthroplasty was evaluated by studying prospectively for a minimum of 14 years (range, 14-17 years), 124 consecutive cementless total knee arthroplasties using a Miller-Galante I prosthesis in 99 patients with a mean age of 62 years who had primary or secondary osteoarthritis. Knee function and roentgenograms were evaluated using the Knee Society criteria. Kaplan-Meier survivorship analysis was conducted. Five patients (five knees) were lost to followup; six patients died with six knees in place. Fifteen knees (15 patients) failed and were revised. Thirteen metal-backed patellas were revised. Eight of these revisions also required exchange of the femoral component, but only one tibial tray was revised. One knee (one patient) was revised for an infection. Of the 98 knees not revised (73 patients) observed throughout this study, the average preoperative knee score was 31 (range, 0-47); postoperatively, the average knee score was 91 (range, 72-100). The average function score improved from 28 (range, 10-45) to 84 (range, 50-100). Twenty-four tibial trays (21%) and twenty femoral components (17%) of the 113 knees studied showed osteolysis. This study indicates that osteointegration of cementless tibial components can be successful with screw fixation, although there is a worrisome incidence of tibial and femoral osteolysis. The overall knee survival rate was 87%; however, the tibial component had a survival of 99%.

It has been reported that demineralized bone matrix (cortical or trabecular bone) contains intrinsic cytokines. In the present study, we tested allogeneic demineralized bone matrix for its capacity to resurface osteochondral defects in a rabbit model with the assumption that the intrinsic cytokines in demineralized bone matrix will facilitate the recruitment of progenitor cells from bone marrow into the defect. It was further assumed that these intrinsic bioactive factors would modulate these cells to differentiate into osteochondrogenic lineage and, thus, functionally repair the osteochondral defect. The biocompatibility of demineralized bone matrix was first tested by loading rabbit bone-marrow-derived mesenchymal stem cells into porous demineralized trabecular bone matrix that was then cultured for 3 days. The cell growth in demineralized trabecular bone matrix was examined by scanning electron microscopy. Loaded rabbit bone-marrow-derived mesenchymal stem cells attached to the trabeculae of demineralized trabecular bone matrix; some cells appeared to be round and others were spread and contacted other cells. Allogeneic rabbit demineralized cortical bone matrix or demineralized trabecular bone matrix was implanted into a full-thickness osteochondral defect in the load-bearing area of the medial femoral condyle of young adult rabbits. At 6 and 12 weeks after surgery, gross and histological examination showed that the defects were repaired up to 95% of their depth. The repair tissue using demineralized cortical bone matrix was composed of subchondral bone and a top layer of cartilage that was smooth and integrated with the adjacent cartilage in most of the specimens. Most of the repair tissue in the defect filled with demineralized trabecular bone matrix had a fibrillated surface without integration with the adjacent cartilage. These results indicate that demineralized cortical bone matrix may be potentially useful to repair osteochondral defects by managing the host's intrinsic reparative cells.

An approach for promoting the adherence of chondrogenic progenitor cells to specific matrix molecules has been tested in a cartilage defect model. Culture-expanded pre-chondrocytes fluorescently labeled with a vital dye were coated by a two-step method wherein lipidated protein G was first allowed to intercalate into cell membranes, and a second incubation in a solution of antibodies to cartilage matrix antigens allowed the binding of the antibodies to the protein G, on the external surface of the cell. The coating technique (termed "cell painting") does not effect cell viability or inhibit growth and chondrogenic potential. Painted cells were then added to rabbit cartilage explants that had a partial-thickness defect, washed, and prepared for histological examination and for confocal microscopy. The histological observations and the confocal observations and fluorescent intensity quantification consistently demonstrated that progenitor cells painted with multiple antibodies were capable of preferential binding to the exposed cartilage matrix within the defect. These results demonstrate that painting cell membranes with antibodies to matrix molecules is an effective method for promoting the adherence of stem or progenitor cells to a cartilage injury site.

This study determined the effects of a plasma-sprayed hydroxyapatite/tricalcium phosphate (HA/TCP) coating on osseointegration of plasma-sprayed titanium alloy implants in a lapine, distal femoral intramedullary model. The effects of the HA/TCP coating were assessed at 1, 3, and 6 months after implant placement. The HA/TCP coating significantly increased new bone apposition onto the implant surfaces at all time points. The ceramic coating also stimulated intramedullary bone formation at the middle and distal levels of the implants. Fluorescent bone labeling indicated that new bone formation occurred primarily during the first 3 months after implantation, with comparatively little activity detected in the latter stages of the study. There was no associated increase in pullout strength at either 3 or 6 months; however, post-pullout evaluation of the implants indicated that the HA/TCP coating itself was not the primary site of construct failure. Rather, failure was most commonly observed through the periprosthetic osseous struts that bridged the medullary cavity. The demonstrated osteoconductive activity of HA/TCP coating on plasma-sprayed titanium alloy implant surfaces may have considerable clinical relevance to early host-implant interactions, by accelerating the establishment of a stable prosthesis-bone interface.

Background: Radiographic measurements of the wear of total hip arthroplasty implants are indirect measurements based on radiographic determinations of the location of the femoral head relative to the acetabular component. Using the simplest case of zero wear, we assessed the reproducibility and accuracy of two software applications designed to quantify wear from clinical radiographs. Methods: After a cobalt-chromium head was glued into the polyethylene liner of a titanium shell, one cross-table lateral radiograph and three anteroposterior pelvic radiographs were made for twelve permutations of acetabular component angulation. The three anteroposterior radiographs differed only with regard to the cephalocaudal positioning of the prosthesis relative to the x-ray tube. To assess method reproducibility, each anteroposterior radiograph was assumed to be both the initial and the latest follow-up radiograph of a wear analysis. To assess method accuracy, each anteroposterior radiograph was paired in a wear analysis with each of the two anteroposterior radiographs made when the component was in the same angulation but at a different cephalocaudal position relative to the tube (one radiograph was the initial follow-up radiograph while the second was the latest follow-up radiograph). The analyses of reproducibility and accuracy were performed both with and without inclusion of the lateral radiograph made with the component in the same angulation. Results: Both methods fared well in the reproducibility analyses, with mean linear and volumetric wear values of 0.00 to 0.07 mm and 0 to 24 mm 3 , respectively. In the accuracy analyses, the mean linear and volumetric wear values derived with the two methods were 0.26 to 0.40 mm and 78 to 126 mm 3 , respectively. Conclusions: Whereas the results of the reproducibility analyses showed that the methods were consistent in determining the relative positions of the head and shell from a given anteroposterior radiograph or pair of anteroposterior and lateral radiographs, the non-zero wear results obtained in the accuracy analyses proved that these positional determinations were often inaccurate. Thus, while contemporary software methods may yield reproducible results, their accuracy is limited by their inability to correctly determine the position of the head relative to the acetabular component. Clinical Relevance: Wear magnitudes obtained in this study often exceeded wear magnitudes that would be expected at five years after implantation of contemporary polyethylenes. Accuracy in determining the relative component positions must be improved to obtain meaningful measurements at early to intermediate follow-up intervals. The inability to strictly control tube and patient positioning magnifies the need for these improvements and largely restricts clinical applicability of the studied methods to later-term analyses.

Cytokine-mediated induction and overexpression of matrix metalloproteinases (MMPs) is recognized as an important factor in the pathogenesis of arthritis. Interleukin (IL)-1 beta is a proinflammatory cytokine that is known to superinduce the expression and production of MMP-13 in many cell types. Phenyl N-tert-butylnitrone (PBN), a spin trap agent, inhibited the IL-1 beta-induced expression of MMP-13 in human osteoarthritis (OA) chondrocytes. Down-regulation of MMP-13 expression correlated with the inhibition of mitogen-activated protein kinase (MAPK) subgroups c-Jun NH2-terminal kinase (JNK) and p38-MAPK activation, accumulation of phospho-c-jun, and the DNA binding activity of activating protein-1 (AP-1). Results of in vitro kinase assays showed that exogenously added PBN completely blocked the c-Jun phosphorylating activity of JNK. Interestingly, using in vitro kinase assay, we also found that chondrocyte p38-MAPK phosphorylate c-Jun and that PBN was not very effective in inhibiting c-Jun phosphorylating activity of p38-MAPK. In addition, PBN did not block the ATF-2 phosphorylating activity of p38-MAPK and Elk-1 phosphorylating activity of extracellular regulated kinase p44/p42 in vitro, indicating that PBN may act selectively to inhibit the phosphorylation of c-Jun in OA chondrocytes. Together, our results for the first time demonstrate that PBN suppresses the IL-1 beta-stimulated expression of MMP-13 in OA chondrocytes and that this was achieved by inhibiting the activation of JNK and AP-1. These results suggest that use of PBN or compounds derived from it may be of potential benefit in inhibiting signaling events associated with cartilage degradation in arthritis.

The key to successful management of an infection at the site of a total knee arthroplasty is an early and accurate diagnosis that allows prompt treatment. Therefore, it is critical that every patient with pain at the site of a total knee arthroplasty is assessed for the presence of infection1. The usual presentation is characterized by constant pain, warmth, and effusion. Erythema is unusual. It is important to elicit the history of the perioperative course that followed the primary total knee replacement: Did the original wound heal without delay? Was there any postoperative drainage? A complete history ( Table I), physical examination, plain radiographs, and other diagnostic studies discussed below are critical to confirm the diagnosis of infection and to rule out other causes of knee pain2. View this table: TABLE I: Risk Factors for Infection Following Total Knee Arthroplasty Aspiration of the affected knee should be among the first diagnostic tests performed3-5. If the first aspirate is negative but a suspicion of infection remains, then at least two additional aspirations should be performed. Any current antibiotic therapy should be sdiscontinued for a minimum of ten days, and the aspiration should then be repeated. The aspirate should be sent for aerobic, anaerobic, and fungal cultures, and a white blood-cell count with differential should be performed. Blood tests should include determination of the erythrocyte sedimentation rate and the C-reactive protein level. The results of aspiration of the knee must be correlated with the results of the physical examination and radiographs for complete assessment of the possibility of infection6. Radionucleotide studies, particularly bisphosphonate scans in conjunction with indium-labeled leukocyte scans, may contribute to a proper diagnosis. A normal radionucleotide scan suggests that loosening or infection is not the likely cause of pain. It must be remembered, however, …

This study compared the effects of hydroxyapatite (HA) coating and biphasic HA/tricalcium-phosphate (HA/TCP) coating on the osseointegration of grit-blasted titanium-alloy implants. Each coated implant was compared with uncoated grit-blasted implants as well. The implants were press-fit into the medullary canal of rabbit femora, and their osseointegration was evaluated 3 to 24 weeks after surgery. The coated implants had significantly (P.05) greater new bone ongrowth than the uncoated implants (HA, 56.1 +/- 3.1%; HA/TCP, 53.8 +/- 2.6%; uncoated, 32.2 +/- 1.4% of the implant perimeter, 12 weeks). Unmineralized tissue (cartilage and osteoid) was seen on the uncoated implants but never on the coated implants. The coated implants had significantly (P.05) greater interfacial shear strength than the uncoated implants (HA, 4.1 +/- 0.4 MPa; HA/TCP, 4.8 +/- 0.5 MPa; uncoated, 2.6 +/- 0.2 MPa, 12 weeks). There was no difference between HA and HA/TCP coating in regard to new bone growth or interfacial shear strength. These data show a comparable enhancement effect of HA and HA/TCP coatings on the osseointegration of titanium-alloy implants.

Objective The proinflammatory cytokine interleukin-1β (IL-1β) induces the production of high levels of nitric oxide (NO) in human chondrocytes. Green tea (Camellia sinensis) polyphenols are potent antiinflammatory agents and have been shown to inhibit NO production in tumor cell lines. In the present study, we examined the effect of epigallocatechin-3-gallate (EGCG), a green tea polyphenol, on IL-1β–induced production of NO in primary human osteoarthritis (OA) chondrocytes. Methods Human chondrocytes were derived from OA cartilage and were treated with EGCG (100 μM) and IL-1β (2 ng/ml) for different periods, and inducible nitric oxide synthase (iNOS) messenger RNA and protein expression was determined by real-time quantitative reverse transcriptase–polymerase chain reaction and Western blotting, respectively. Production of NO was determined as nitrite in culture supernatant. Activation and translocation of nuclear factor κB (NF-κB), levels of inhibitor of nuclear factor κB (IκB), and NF-κB DNA binding activity were determined by Western blotting and a highly sensitive and specific enzyme-linked immunosorbent assay. Activity of IκB kinase was determined using in vitro kinase assay. Results Human chondrocytes cotreated with EGCG produced significantly less NO compared with chondrocytes stimulated with IL-1β alone (P < 0.005). The inhibition of NO production correlated with the suppression of induction and expression of NF-κB–dependent gene iNOS. EGCG inhibited the activation and translocation of NF-κB to the nucleus by suppressing the degradation of its inhibitory protein IκBα in the cytoplasm. Conclusion Our results indicate that EGCG inhibits the IL-1β–induced production of NO in human chondrocytes by interfering with the activation of NF-κB through a novel mechanism. Our data further suggest that EGCG may be a therapeutically effective inhibitor of IL-1β–induced inflammatory effects that are dependent on NF-κB activation in human OA chondrocytes.

The major cause of orthopaedic implant loosening is thought to be accelerated osteoclastic bone resorption due to the action of cytokines produced in response to phagocytosis of implant-derived wear particles. This accelerated osteoclastic bone resorption could be due to increases in any of the following processes: recruitment of osteoclast precursors to the local microenvironment, differentiation of precursors into mature multinucleated osteoclasts. activation of mature osteoclasts, and/or survival of osteoclasts. Our studies have focused on differentiation and survival to complement work by others who have focused on recruitment of precursors and activation. Taken together, our studies and those of other investigators provide strong evidence that increased recruitment of osteoclast precursors and their subsequent differentiation play major roles in wear particle-induced osteolysis. In contrast, increased osteoclast activation and survival appear to play minor roles. These studies suggest that development of therapeutic interventions that reduce either recruitment or differentiation of osteoclast precursors would improve the performance of orthopaedic implants.

The most important factor contributing to short-term and long-term success of cementless total joint arthroplasties is osseointegration. Osseointegration leads to a direct structural and functional connection between living bone and the surface of an implant. Surface contaminants may remain on orthopaedic implants after sterilization procedures and impair osseointegration. For example, specific lots of hip replacement Sulzer Inter-OP(TM) acetabular shells that were associated with impaired osseointegration and early failure rates were found to be contaminated with both bacterial debris and machine oil residues. However, the effect of machine oil on implant integration is unknown. Therefore, the goal of this study was to determine if machine oil inhibits the osseointegration of orthopaedic implants. To test this hypothesis in vivo we used our murine model of osseointegration where titanium alloy implants are implanted into a unicortical pilot hole in the mid-diaphysis of the femur. We found that machine oil inhibited bone-to-implant contact and biomechanical pullout measures. Machine oil on titanium alloy discs inhibited early stages of MC3T3-E1 osteogenesis in vitro such as attachment and spreading. Inhibition of osteoblast attachment and spreading occurred in both areas with and without detectable oil. Osteoblast growth was in turn inhibited on discs with machine oil due to both a decrease in proliferation and an increase in cell death. Later stages of osteogenic differentiation and mineralization on titanium alloy discs were also inhibited. Thus, machine oil can inhibit osseointegration through cell autonomous effects on osteoblast cells. These results support routine testing by manufacturers of machine oil residues on orthopaedic implants.

More than 33 million musculoskeletal injuries occur in the United States each year. Bone is capable of regeneration, and defects often heal spontaneously. However, cartilage, tendon, and ligament injuries usually heal by scar formation, which is inferior to the native tissue. Tissue engineering approaches to recapitulate the embryonic events that result in the development of native tissue have the potential to heal these tissues. The goal of tissue engineering is to generate biologic substitutes for repair, restoration and/or replacement of injured tissue. Typically, these approaches employ a combination of one or more of three components: cells (tissue function), growth factors and differentiation stimuli (lineage direction), and/or a scaffolding matrix (cell attachment and/or structural architecture). The generated construct should be site specific and integrate well at the host-graft interface.

Aseptic loosening of orthopedic implants is thought to be caused primarily by osteoclast differentiation induced by bone resorptive cytokines produced in response to phagocytosis of implant-derived wear particles. This study examined whether adherent endotoxin on the wear particles is responsible for inducing osteoclast differentiation as well as production of interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor a (TNF-alpha). Removal of adherent endotoxin almost completely inhibited the responses to titanium (Ti) particles by both murine marrow cells and human peripheral blood monocytes. In vivo experiments showed that endotoxin removal reduced particle-induced osteolysis by 50-70%. Addition of lipopolysaccharide (LPS) to the "endotoxin-free" particles restored their ability to induce cytokine production and osteoclast differentiation in vitro. Moreover, marrow cells from mice that are hyporesponsive to endotoxin because of mutation of Toll-like receptor 4 induced significantly less cytokine production and osteoclast differentiation in response to Ti particles with adherent endotoxin than did marrow cells from normoresponsive mice. This mutation also resulted in significantly less particle-induced osteolysis in vivo. Taken together, these results show that adherent endotoxin is involved in many of the biological responses induced by orthopedic wear particles and should stimulate development of new approaches designed to reduce the activity of adherent endotoxin in patients with orthopedic implants.