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Two major issues in total joint arthroplasty are loosening of implants and osteolysis caused by wear particle-induced inflammation. Wear particles stimulate the release of pro-inflammatory cytokines, chemokines, and other inflammatory mediators from macrophages and other cells. Although the biological response of macrophages to wear debris is well established, the role of other cell types such as natural killer T lymphocytes (NKT) and dendritic cells (DCs) is limited. Here we show that ultra-high molecular weight polyethylene (UHMWPE) particles stimulate NKT cells to secrete Interferon-γ (IFN-γ); coculture with DCs further enhanced IFN-γ secretion. Furthermore, UHMWPE particles did not stimulate NKT cells to secrete IL-4, while the NKT cell natural ligand α-galactosylceramide (α-GalCer) treatment in the coculture system significantly enhanced both IFN-γ and IL-4 expression by NKT cells. Comparatively, NKT cells and/or DCs exposed to polymethylmethacrylate particles did not stimulate IFN-γ or IL-4 expression. Mouse bone marrow derived macrophage polarization by lipopolysaccharide and conditioned medium from NKT cells and/or DCs exposed to UHMWPE particles increased tumor necrosis factor-α (TNF-α), but reduced arginase-1 expression in macrophages. The current findings indicate that UHMWPE particles stimulate NKT cells/DCs to produce pro-inflammatory cytokines; this pathway is a novel therapeutic target to mitigate wear particle induced peri-prosthetic osteolysis.

This symposium is comprised of selected papers delivered at the 2012 Fall (Closed) Meeting of the Hip Society in Rochester, MN, and the Open Scientific Meeting of the Hip Society, in conjunction with the 2013 Annual Meeting of the American Academy of Orthopaedic Surgeons (AAOS) in Chicago. These meetings focused on current clinical and applied research, and elucidated new information on subjects such as alternative bearing surfaces, outcome of different prosthesis designs, surgical techniques for hip arthroplasty, hip joint preserving procedures, and complications such as infection and thromboembolic disease. During the last decade, metal-on-metal (MOM) articulations have seen a dramatic decline worldwide due to adverse effects associated with the generation of nanometer-sized metal particulates and ions. New studies suggest that the development of pseudotumors occurs even in well-functioning MOM implants, and that metal ion levels, the presence of a pseudotumor, and the clinical function of the patient are not exactly concordant. This fact points to the need for ongoing clinical and laboratory surveillance of patients with MOM implants. Additionally, the production of metallic byproducts and adverse local tissue reactions are now being reported in some patients with total hip replacements with large femoral heads articulating with a highly cross-linked polyethylene, and with modular femoral necks. These patients will also need close surveillance. The success of other bearing surfaces continues to be reported, including ceramic-on-ceramic, ceramic-on-highly crosslinked polyethylene. Although the material properties of these newer bearings are vastly improved, these implants must be implanted with precision to avoid complications such as striped wear, squeaking, impingement, chipping, breakage, and incomplete seating. Implant designs with modular parts offer more options for the surgeon to reconstruct the hip optimally, taking into account factors such as femoral configuration, length, offset, bone quality, the presence of a periprosthetic fracture. These implants offer surgeons new capabilities for optimizing and restoring normal hip biomechanics. However, modular junctions may fail mechanically or corrode, yielding new problems. Long-term studies are needed to compare the outcomes of newer modular designs with more established nonmodular implants. Perioperative and late infections are dreaded complications that the reconstructive surgeon is facing with increasing frequency. New methods for expeditious and accurate diagnosis of infection are forthcoming, including laboratory, cellular and molecular tests. Indeed, many of our “single-stage” revisions for diagnoses such as aseptic loosening, polyethylene wear, and recurrent dislocation may in fact be septic cases, if the effort is taken to aggressively culture the operative field and implant for longer periods of time. Current research is examining novel methods of prevention of infection via local and systemic means (implant coatings, enhanced patient prophylactic measures) to mitigate this complication. Recently, both the AAOS and the American College of Chest Physicians have updated their guidelines for prevention of thromboembolic disease after hip arthroplasty. These new guidelines emphasized individualization of prophylaxis based on patient characteristics and complexity of the procedure. Newer physical and pharmacologic agents have entered the marketplace since the previous guidelines, and now have a prominent role. In some patients, hip preservation procedures may be a better option than hip replacement. Patient selection and surgical experience may be the most important determinants of outcome. Further research in this area is needed, as these younger patients (and their hips) must endure a long life following their surgical procedure. This symposium underscores the important research that members of the Hip Society and their collaborators undertake, and serves a valuable educational purpose for surgeons interested in disorders of the hip. All studies reported in this symposium have undergone rigorous peer review. The members of the Hip Society and I (Fig. 1) are pleased to share their research. Fig. 1 Stuart B. Goodman MD, PhD.

This case report and literature review examines whether closed reduction is a viable option to manage hip dislocation when the patient has a constrained liner. Introduction Dislocation after total hip arthroplasty (THA) ranges from less than 1% to 6% of primary cases [1] and from 15% to 30% of revision cases [2]. Unfortunately, the success rate of non-operative treatment of dislocation after THA can be unreliable, and a third of such patients have recurrences [1]. Surgical procedures used to treat instability and dislocation include: •Tightening the abductor musculature •Removing sources of impingement •Repositioning malaligned components •Using acetabular liners with elevated rims Such treatments fail in 30% to 50% of patients, however [3]. The use of constrained liners, which relies on a locking mechanism to capture the femoral head, has been developed to help manage this problem [4]. Despite such efforts, patients continue to be at high risk for instability, and 3% to 18% experience recurrent dislocation even after constrained components have been implanted [5,6]. Generally, open surgical reduction is thought to be the only available treatment for such cases. However, this compromises the integrity of the joint and exposes the patient to the additional risk of surgery [7]. Several authors have reported closed reduction for dislocation of a constrained liner [7-13]. Constrained acetabular liners are currently available in various designs, with differences in the locking mechanisms. To our knowledge, ours is the first reported case of a successful closed reduction of a dislocated constrained THA using a Trilogy Acetabular System Constrained liner (Zimmer, Inc, Warsaw, Indiana, USA). The study protocol adhered to the ethics guidelines of the 1975 Declaration of Helsinki, and the study was approved by the Institutional Review Board of Stanford University.

Aseptic loosening and osteolysis are the most frequent late complications of total hip arthroplasty (THA) leading to revision of the prosthesis. This review aims to demonstrate how histopathological studies contribute to our understanding of the mechanisms of aseptic loosening/osteolysis development. Only studies analysing periprosthetic tissues retrieved from failed implants in humans were included. Data from 101 studies (5532 patients with failure of THA implants) published in English or German between 1974 and 2013 were included. "Control" samples were reported in 45 of the 101 studies. The most frequently examined tissues were the bone-implant interface membrane and pseudosynovial tissues. Histopathological studies contribute importantly to determination of key cell populations underlying the biological mechanisms of aseptic loosening and osteolysis. The studies demonstrated the key molecules of the host response at the protein level (chemokines, cytokines, nitric oxide metabolites, metalloproteinases). However, these studies also have important limitations. Tissues harvested at revision surgery reflect specifically end-stage failure and may not adequately reveal the evolution of pathophysiological events that lead to prosthetic loosening and osteolysis. One possible solution is to examine tissues harvested from stable total hip arthroplasties that have been revised at various time periods due to dislocation or periprosthetic fracture in multicenter studies.

Bearing surfaces for joint replacements have undergone many recent changes. The traditional metal-on-conventional polyethylene bearings, which were associated with a chronic inflammatory response to wear debris and osteolysis, have been replaced in many clinical scenarios, by highly cross-lined polyethylene, new ceramics, and metal-on-metal articulations. Each bearing couple has known advantages and disadvantages. The overall goal is to provide the patient with a long-lasting articulation that will allow full work and recreational activities, with minimal/no adverse events. Although we have not yet achieved this goal, highly cross-lined polyethylene and ceramic bearing couples in particular have facilitated new approaches to joint replacement that have demonstrated increased durability and improved patient outcomes.

Revision total hip arthroplasty (THA) in patients with juvenile idiopathic arthritis (JIA) is challenging as a result of the patient's young age, systemic disease, multiple affected joints, small proportions, and bone loss. The intermediate- to long-term results of these surgeries remain unknown.The purpose of this study is to determine the (1) functional outcomes; (2) surgical complications; and (3) frequency of reoperation or revision after revision THA for JIA.We reviewed the records of all patients from one center who underwent revision THA for JIA who had a minimum of 5 years of followup (mean, 9 years; range, 5-19 years). This resulted in a series of 24 revision THAs in 15 patients. All patients were Charnley Class C. Age at revision averaged 35 years (range, 21-53 years). The 20 acetabular and 12 femoral revision components included 15 cementless cups, five reconstruction/roof rings with a cemented cup, and four cemented and eight cementless femoral stems.The Harris hip scores improved from 54 (range, 34-85) to 77 (range, 37-100) (p0.001). Complications included two proximal femoral fractures associated with severe osteolysis and one sciatic nerve palsy in a patient with severe acetabular deficiency. A total of seven hips (29%) required reoperation or revision surgery, including three for infection (one early and two late) and four for mechanical loosening.Revision THA in JIA is very challenging owing to patients' small proportions and compromised bone stock. The intraoperative and early complication rates are relatively high. Prognosis for long-term survivorship is guarded; limiting factors include periprosthetic osteolysis associated with older implants that used conventional polyethylene and cemented stems.

Porous tantalum acetabular implants provide a potential solution for dealing with significant acetabular bone loss. This study reviews 24 acetabular revisions using tantalum implants for Paprosky type 3 and 4 defects. The mean Harris Hip Score improved from 35 ± 19 (range, 4-71) to 88 ± 14 (range, 41-100), p0.0001. Postoperative radiographs showed radiolucent lines in 14 hips with a mean width of 1.3 ± 1.0 mm (range, 0.27-4.37 mm). No gaps enlarged and 71% of them disappeared at a mean of 13 ± 10 months (range, 3-29 months). At a mean follow-up of 37 ± 14 months (range, 24-66 months), 22 reconstructions showed radiograpic evidence of osseointegration (92%). The two failures were secondary to septic loosening. When dealing with severe acetabular bone loss, porous tantalum acetabular components show promising short-term results.

Treatment of critical size bone defects is challenging. Recent studies showed that the cytokine stromal cell-derived factor 1 alpha (SDF-1α) has potential to improve the bone regenerative effect of low bone morphogenetic protein 2 (BMP-2) concentrations. The goal of this study was to demonstrate the combined effect of SDF-1α and BMP-2 on bone regeneration and stem cell recruitment using a critical size femoral bone defect model. A total of 72 mice were randomized to six groups. External fixators were implanted onto the right femur of each mouse and 3 mm defects were created. Depending on the group affiliation, adenovirally activated fat tissue grafts expressing SDF-1α or/and BMP-2 were implanted at the defect site. One day after operation, 1×106 murine mesenchymal stromal cells (MSCs), lentivirally transduced to express the gene enhanced green fluorescent protein (eGFP), firefly luciferase, and CXCR4 were injected systemically in selected groups. Migration of the injected MSCs was observed by bioluminescence imaging on days 0, 2, 4, 6, 8, 10, 12, 14, 21, 28, and 42. After 6 weeks, animals were euthanized and 80 μm CT-scans were performed. For histological investigations, hematoxylin and eosin-, tartrate-resistant acid phosphatase-, alkaline phosphatase-, and anti-eGFP-stained sections were prepared. BMP-2 and SDF-1α combined at the defect site increased bone volume (BV) (2.72 mm3; 95% CI 1.95–3.49 mm3) compared with the negative control group (1.80 mm3; 95% CI 1.56–2.04 mm3; p

Biomaterial-induced tissue responses in patients with total joint replacement are associated with the generation of wear particles, which may lead to chronic inflammation and local bone destruction (periprosthetic osteolysis). Inflammatory reactions associated with wear particles are mediated by several important signaling pathways, the most important of which involves the transcription factor NF-κB. NF-κB activation is essential for macrophage recruitment and maturation, as well as the production of pro-inflammatory cytokines and chemokines such as TNF-α, IL-1β, IL-6, MCP1, etc. In addition, NF-κB activation contributes to osteoclast differentiation and maturation via RANK/RANKL signaling, which increases bone destruction and reduces bone formation. Targeting individual downstream cytokines directly (such as TNF-α or IL-1β) may not effectively prevent wear particle induced osteolysis. A more logical upstream therapeutic approach may be provided by direct modulation of the core IκB/IKKα/β/NF-κB signaling pathway in the local environment, however, the timing, dose, and strategy for administration should be considered. Suppression of chronic inflammation via inhibition of NF-κB activity in patients with malfunctioning joint replacements may be an effective strategy to mitigate wear particle induced periprosthetic osteolysis.

Total joint replacement (TJR) is a common and effective surgical procedure for hip or knee joint reconstruction. However, the production of wear particles is inevitable for all TJRs, which activates macrophages and initiates an inflammatory cascade often resulting in bone loss, prosthetic loosening and eventual TJR failure. Macrophage Chemoattractant Protein-1 (MCP-1) is one of the most potent cytokines responsible for macrophage cell recruitment, and previous studies suggest that mutant MCP-1 proteins such as 7ND may be used as a decoy drug to block the receptor and reduce inflammatory cell recruitment. Here we report the development of a biodegradable, layer-by-layer (LBL) coating platform that allows efficient loading and controlled release of 7ND proteins from the surface of orthopaedic implants using as few as 14 layers. Scanning electron microscopy and fluorescence imaging confirmed effective coating using the LBL procedure on titanium rods. 7ND protein loading concentration and release kinetics can be modulated by varying the polyelectrolytes of choice, the polymer chemistry, the pH of the polyelectrolyte solution, and the degradation rate of the LBL assembly. The released 7ND from LBL coating retained its bioactivity and effectively reduced macrophage migration towards MCP-1. Finally, the LBL coating remained intact following a femoral rod implantation procedure as determined by immunostaining of the 7ND coating. The LBL platform reported herein may be applied for in situ controlled release of 7ND protein from orthopaedic implants, to reduce wear particle-induced inflammatory responses in an effort to prolong the lifetime of implants.

Hip resurfacing with metal-on-metal bearing surfaces was developed for the younger, more active patient with end-stage degenerative arthritis and relatively normal osseous anatomy. Some clinicians embraced the advantages of this surgical procedure, namely, preservation of more of the proximal aspect of the femur compared with standard total hip replacement, the use of a larger femoral head potentially mitigating the prevalence of dislocation, and less restriction on impact loading activities due to the use of a hard-on-hard bearing couple. The operation was more technically demanding for the surgeon, as fewer hip resurfacings are performed compared with conventional hip replacements. Despite this, the initial clinical outcomes, mostly from designer and higher-volume surgeons, were very encouraging1. As more patients learned of and asked for this procedure, increasing numbers of surgeons began performing this technique. As experience grew, adverse outcomes were being reported, with some due to deficiencies in the design of specific components or suboptimal …

Historically, polyethylene wear and its sequelae (osteolysis, late instability, aseptic loosening) were common causes for revision total knee arthroplasty (TKA). Recently, polyethylene manufacturing has become more consistent; furthermore, a clearer understanding of the importance of oxidation on polyethylene performance led to packaging of the polyethylene bearings in an inert environment. This improved the quality and consistency of polyethylene used in TKA, raising the question of whether different failure modes now predominate after TKA.The purpose of this study was to determine the current reasons for (1) early and (2) late failures after TKA at one high-volume arthroplasty center.We reviewed all first-time revision TKAs performed between 2001 and 2011 at one institution, yielding a group of 253 revision TKAs in 251 patients. Mean age at the time of revision was 64 years (SD 10 years). Mean time to revision was 35 months (SD 23 months). Preoperative evaluations, laboratory data, radiographs, and intraoperative findings were used to determine causes for revision. Early failure was defined as revision within 2 years of the index procedure. The primary failure mechanism was determined by the operating surgeon.Early failure accounted for 46% (116 of 253) of all revisions with infection (28 of 116 [24%]), instability (30 of 116 [26%]), and stiffness (21 of 116 [18%]) being the leading causes. Late failure accounted for 54% (137 of 253) of all revisions with the most common causes including infection (34 of 137 [25%]), instability (24 of 137 [18%]), and stiffness (19 of 253 [14%]). Polyethylene wear was implicated as the failure mechanism in 2% of early cases (two of 116) and 9% of late cases (13 of 137).In contrast to previous studies, wear-related implant failure in TKA was relatively uncommon in this series. Changes in polyethylene manufacturing, sterilization, and storage may have accounted for some of this difference; however, longer-term followup will be required to verify this finding. Infection, instability, and stiffness represent the most common causes of early and late failure. Strategies to improve outcomes in TKA should be aimed at infection prophylaxis and treatment, surgical technique, and patient selection.Level III, therapeutic study. See Instructions for Authors for a complete description of levels of evidence.

Gene therapy provides a powerful tool for regulating cellular processes and tissue repair. Minicircle (MC) DNA are supercoiled DNA molecules free of bacterial plasmid backbone elements, and have been reported to enhance prolonged gene expression compared to conventional plasmids. Despite the great promise of MC DNA for gene therapy, methods for safe and efficient MC DNA delivery remain lacking. To overcome this bottleneck, here we report the development of a poly (β-amino ester) (PBAE)-based, biodegradable nanoparticulate platform for efficient delivery of MC DNA driven by an Ubc promoter in vitro and in vivo. By synthesizing and screening a small library of 18 PBAE polymers with different backbone and end-group chemistry, we identified lead cationic PBAE structures that can complex with minicircle DNA to form nanoparticles, and delivery efficiency can be further modulated by tuning PBAE chemistry. Using human embryonic kidney 293 cells and mouse embryonic fibroblasts as model cell types, we identified a few PBAE polymers that allow efficient MC delivery at levels that are comparable or even surpassing Lipofectamine 2000. The biodegradable nature of PBAE-based nanoparticles facilitates in vivo applications and clinical translation. When injected via intraperitoneal route in vivo, MC alone resulted in high transgene expression and a lead PBAE/MC nanoparticle formulation achieved a further 2-fold increase in protein expression compared to MC alone. Together, our results highlight the promise of PBAE-based nanoparticles as promising non-viral gene carriers for MC delivery, which may provide a valuable tool for broad applications of MC DNA-based gene therapy.

The purpose of the present study was to characterize the underlying causes that lead to instability after total knee arthroplasty (TKA). We reviewed 83 revision TKAs (79 patients) performed for instability. After detailed analysis of patient's history, physical examination, operative report and radiographs, we identified six categories: flexion/extension gap mismatch, component malposition, isolated ligament insufficiency, extensor mechanism insufficiency, component loosening, and global instability. Twenty-five knees presented with multi-factorial instability. When these knees were classified according to the most fundamental category, each category above included 24, 12, 11, 10, 10 and 16 knees respectively. The unstable TKA may result from a variety of distinct etiologies which must be identified and treated at the time of revision. The revision TKA could be tailored to the specific causes.

Implants are widely used for orthopaedic applications such as fixing fractures, repairing non-unions, obtaining a joint arthrodesis, total joint arthroplasty, spinal reconstruction, and soft tissue anchorage. Previously, orthopaedic implants were designed simply as mechanical devices; the biological aspects of the implant were a byproduct of stable internal/external fixation of the device to the surrounding bone or soft tissue. More recently, biologic coatings have been incorporated into orthopaedic implants in order to modulate the surrounding biological environment. This opinion article reviews current and potential future use of biologic coatings for orthopaedic implants to facilitate osseointegration and mitigate possible adverse tissue responses including the foreign body reaction and implant infection. While many of these coatings are still in the preclinical testing stage, bioengineers, material scientists and surgeons continue to explore surface coatings as a means of improving clinical outcome of patients undergoing orthopaedic surgery.

The pneumatic tourniquet produces ischemic changes in limbs. The effects of tourniquet release on systemic blood pressure and metabolic parameters were studied in 11 adult patients undergoing total knee replacement under general anesthesia. Mean arterial pressure (MAP) decreased rapidly after the release of the tourniquet, becoming significant at 3 min and remaining significantly depressed up to 15 min post release. Arterial pH, PaO2, PaCO2, lactate acid, and potassium changed significantly after the release, but normalized within 30 min. These results are notably different from a previous study in a similar patient population undergoing knee replacement under epidural anesthesia. Compared to patients under epidural anesthesia, patients receiving general anesthesia with mechanical ventilation are unable to compensate for the metabolic load caused by the tourniquet release, as the latter group are unable to alter their ventilatory rate. In elderly patients with decreased cardio-pulmonary reserve, this may be of clinical importance.

Early reduction and rigid fixation of unstable vertical shear pelvic fractures has been shown to decrease the incidence of late sequelae and facilitate early mobilization. The results of fixation of the posterior pelvic ring without anterior fixation are unknown. The purpose of this study was to perform a biomechanical comparison of the most frequently used techniques of posterior fixation for unstable pelvic sacroiliac dislocations in conjunction with ipsilateral rami fractures, i.e., an unstable vertical shear injury. The four methods of posterior fixation tested included sacroiliac (SI) screws, anterior SI plates, transiliac bars, and a combination of SI screws and transiliac bars. Six cadaveric pelvises were tested in axial compression and torsion on a biaxial servohydraulic testing machine. Compared to the intact pelvis, single posterior methods of fixation provided approximately 70-85% resistance to axial and torsional loading. By combining SI screws with transiliac bars, approximately 90% of intact pelvic stability was achieved. Our results suggest that rigid posterior fixation of sacroiliac dislocations alone may obviate the need for additional complex anterior surgical procedures to fix rami fractures.

Wear debris has been implicated in the pathogenesis of loosening and osteolysis of total joint replacements by stimulating a foreign body and chronic inflammatory reaction capable of bone resorption. Whether increasing concentrations of wear particles have an adverse biological effect on bone has not been elucidated. We performed a histomorphological and semi-quantitative morphometric analysis of the reaction of bone to different concentrations of phagocytosable particles of high-density polyethylene (HDPE) and titanium 6-aluminium 4-vanadium alloy (Ti-6Al-4V) implanted in the rabbit tibia. The Ti-6Al-4V particles had a diameter of 4.0 +/- 4.4 microns (mean +/- SD); the HDPE particles averaged 4.7 +/- 2.1 microns. Suspensions of 10(6)-10(9) particles per ml were mixed in saline, sterilized, and introduced through a drill hole into the proximal tibia of 30 mature female rabbits. Controls included drilled, but non-implantable limbs. The animals were killed at 16 weeks and histological sections were made of the implant area. Histomorphological assessment was carried out using an interactive image analysis system. The parameters assessed included the presence of histiocytes, foreign body giant cells and inflammatory cells, the location and number of particles, the presence of haematopoeitic elements, fat or necrosis of the marrow, whether healing of the cortical window had taken place, and whether there was evidence of formation or resorption of bone by the periosteum, cortex and marrow. A semi-quantitative rating system was employed. Phagocytosable particles of Ti-6Al-4V and HDPE, in concentrations of 10(6)-10(9) particles per ml, evoked a histiocytic reaction without extensive fibrosis, necrosis or granuloma formation. This reaction occurred without disturbing the normal repair processes of bone formation and resorption to the surgical insult. A clear dose-response effect on the histological parameters assessed in this study was not noted. Using the present model, by 16 weeks, a similar "one time' particle load could be accommodated. The ongoing generation of particulate debris over a more extended period of time might be necessary before the remodelling processes of bone would be disturbed.

Previous studies have attempted to define the biologic properties of the bone-implant interface using a single specimen harvested from the periprosthetic tissues. The purpose of this study was to examine the heterogeneity in cellular and cytokine profiles of multiple samples taken from the tissues surrounding revised hip prostheses. Clinical and radiographic data for nine patients undergoing surgical revision was gathered prospectively. Three tissue samples were taken systematically from the acetabular and/or femoral bed. Morphologic characteristics of the tissues were assessed using hematoxylin and eosin-stained sections. Immunohistochemical staining was performed using monoclonal antibodies to identify macrophages (EMB11 and CD68); activated macrophages (Leu M3); total T lymphocytes (Leu 4 and T11); T-helper lymphocytes (Leu 3A and CD4); cytotoxic/suppressor T lymphocytes (Leu 2A and CD3); and fibroblasts (5B5). In situ hybridization was used to identify the mRNA for specific proteins: interleukin (IL)1 alpha and -beta, IL-2, IL-6, transforming growth factor beta, tumor necrosis factor alpha (TNF alpha), platelet-derived growth factor alpha (PDGF alpha), and interferon gamma. A quantitative assessment was performed for each section by calculating the percentage of positively staining cells using a light microscope and grid-counting technique. A random effect analysis of variance was calculated to determine both the variance between samples within each patient and the variance between different patients. Standard deviations contributed by sampling variance and patient variance were calculated and an F test was applied. Tissue samples taken from different regions of the bone-prosthesis interface showed marked heterogeneity in cellular and cytokine profiles. Critical F values indicating a statistically significant degree of variance between different tissue samples were exceeded for macrophages, cytotoxic/suppressor T lymphocytes, and T-helper lymphocytes. The cytokine profile was significantly different for IL-2, PDGF alpha, and TNF alpha. This tissue heterogeneity may be due to different mechanical and biologic environments along the bone-prosthesis interface. Thus, caution must be exercised in defining the biologic properties of the tissue surrounding revised prostheses according to a single biopsy.

This study investigated effects of different sizes, concentrations, volumes, and surface areas of polymethylmethacrylate (PMMA) particles on human macrophages. Adherent peripheral blood monocytes isolated from five healthy individuals were exposed for 48 h to phagocytosable (0.325 micron and 5.5 microns) and nonphagocytosable (200 microns) spherical particles. Each particle size was tested over a range of concentrations (10(4)-10(11) particles per milliliter [0.325 micron], 10(2)-10(7) particles per milliliter [5.5 microns], 10(1)-10(4) particles per milliliter [200 microns]) to provide overlap in number, volume, and surface area. Primary human monocyte/macrophages were cultured in macrophage serum-free medium and 5% fetal calf serum. Macrophage viability was assessed by 3H-thymidine uptake and activation was quantified by release of interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, prostaglandin E2 (PGE2), and the lysosomal enzyme hexosaminidase. Medium alone served as a negative control; lipopolysaccharide (10 micrograms/mL) was also tested. PMMA particles were not toxic to human macrophages at any concentration tested. The smallest phagocytosable particles (0.325 micron) stimulated the release of interleukin-1 beta, interleukin-6, prostaglandin E2, and hexosaminidase at concentrations of 10(10)-10(11) particles/mL. The release of cytokines, PGE2, and hexosaminidase depended on the size, concentration, surface area, and volume of the phagocytosable particles. This study demonstrates that PMMA particle load Mi.e., the concentration of phagocytosable particles per tissue volume, characterized by size, surface area, and volume, rather than simply particle number-determines the degree of macrophage activation.

Particles similar to those generated from joint replacements affect net bone formation within the Bone Harvest Chamber in rabbits. Whether these effects depend on the concentration of particulate materials is unknown. In this study, we performed a histomorphologic and morphometric analysis of net bone formation in the Bone Harvest Chamber in the presence of different concentrations of phagocytosable particles of high density polyethylene and titanium 6-aluminum 4-vanadium alloy. Chambers were implanted in 9 mature New Zealand white rabbits bilaterally. Concentrations of 10(6), 10(7) and 10(8) polyethylene particles/mL, and 10(8) and 10(9) particles/ mL of titanium alloy in 1% sodium hyaluronate carrier were implanted for 3-week periods in sequence in each of the chambers. 3-week control periods in which nothing was implanted in the chamber were included between the treatments. Increasing concentrations of polyethylene particles were associated with a more marked foreign body response and fibrosis. Net bone formation for the three polyethylene doses was reduced by 11%, 21% and 33% of controls, respectively. For titanium alloy, net bone formation was reduced by 8% and 56% of controls, for concentrations of 10(8) and 10(9) particles/mL, respectively. Our findings suggest possible adverse effects of wear debris on net bone formation and bony remodeling in the prosthetic bed, when concentrations of specific particles reach critical local levels.

Short periods of strain have effects on tissue differentiation in a skeletal defect. Little is known about the importance of the duration of such periods. The authors compared 2 short daily periods of strain pulses that differed only by their duration. This was done by using the micromotion chamber, which is a titanium implant with a transverse intraosseous canal. Fibrous tissue forms in the canal and then is replaced by bone through membranous (metaplastic) ossification. The tissue in the canal can be exposed to cyclic deformation. The chamber allows harvest of the tissue within the canal without disturbing the outer parts of the implant or the surrounding bone, thus enabling repeated experiments in the same animal. Chambers were inserted in 6 rabbits and repeatedly harvested at 3-week intervals. Between harvests, the chambers were subjected to either no motion, 20 cycles once daily during 20 seconds (1 Hz), or 20 cycles once daily during 120 seconds (0.17 Hz). Altogether 39 harvested specimens were studied. The 20-second treatment tended to increase the amount of ingrown bone as compared with no motion, whereas the 120-second treatment caused a marked decrease in bone formation and increase in fibrous tissue. Because the acute tissue trauma appears similar with both deformation treatments, it would appear that the increased fibrous tissue formation with the longer deformation time is caused by the parameters of tissue deformation and not by increased tissue damage.

In the Swedish Knee Arthroplasty Study, all 699 Oxford meniscal bearing cemented unicompartmental prostheses (Biomet, Bridgend, UK) were identified and analyzed regarding failure pattern and compared with all Marmor prostheses (Smith & Nephew Richards, Orthez, France) and with a time-, age-, and sex-matched subset of Marmor prostheses using survival statistics expressed as cumulative revision rates. After 1 year there was already a higher rate, and after 6 years the rate of the Oxford group was more than twice that of the Marmor group. There were 50 revisions in the Oxford group: dislocating meniscus in 16, loosening of the femoral component in 6, tibial component in 4, both components in 4, contralateral arthrosis in 10, infection in 4, and technical failure with instability, pain, and/or impingement of the meniscal bearing anterior in the femoral condyle in 6. It is still unclear if the design with the sliding menisci will, in the long turn, reduce wear and loosening, thereby compensating for the initially inferior results. It is recommended that until this question is clarified, the Oxford knee should be used on a limited scale for long-term comparative studies only.

The purpose of this study was to determine whether small, phagocytosable particles of titanium alloy (Ti) and high-density polyethylene (HDPE) have an adverse effect on bone ingrowth. The bone harvest chamber (BHC) was implanted bilaterally in the proximal tibial metaphysis of six mature rabbits. The BHC has a transverse 1-mm wide pore providing a continuous canal through the chamber for tissue ingrowth. After an initial 6-week period for osseointegration of the BHC, the contents of the canal were harvested repeatedly at 3 weekly intervals. This could be done with the chamber in place, without disturbing its exterior surface or the surrounding bone. The carrier solution, 1% sodium hyaluronate (Healon) was implanted first. In subsequent implantations, Healon was mixed with particles of HDPE or Ti averaging 4.7 ± 2.1 and 3.0 ± 2.6 μm, respectively. The contralateral chamber was left empty and served as a control. The chambers were harvested repeatedly, alternating experimental and control sides. The sections from the control side, and those containing Healon alone demonstrated extensive trabecular bone in a fibrovascular stroma. The sections containing Ti alloy particles were qualitatively and quantitatively similar to the control sections and those containing Healon, except for the presence of small black granules of Ti alloy, dispersed in the fibrovascular stroma or phagocytosed by scattered macrophages. The sections containing HDPE particles were infiltrated and engulfed by mononuclear and multinuclear histiocytic cells in a highly fibrous stroma. The majority of the multinucleated cells present were interpreted as being foreign body giant cells. Less trabecular bone was seen in the HDPE group compared to the other groups. Using the parameters chosen for this experiment, it would appear that small, phagocytosable HDPE particles are more deleterious to net formation of bone compared to particles of Ti alloy. © 1995 John Wiley & Sons, Inc.

Minimal incision total knee arthroplasty (MI TKA) was developed with the potential to decrease surgical trauma, pain, and recovery time. While this procedure has increased in popularity, some surgeons have questioned its safety and long-term efficacy. In this study 58 consecutive revision total knee arthroplasties (TKAs) (57 patients) performed at one academic medical center from 2006 to 2008 are reviewed. Prospectively collected clinical and radiographic data included: incision length, gender, age, time to revision surgery, and primary diagnosis at time of revision. Of these, 34 knees involving infection and rerevision were excluded. Of the remaining 24 knees, 11 knees that met inclusion criteria had undergone MI TKA. There were no differences between the groups with regard to age, diagnosis, body mass index, and gender. Average time to revision was shorter for the MI TKA patients (29 vs. 65 months, p0.032, odds ratio 14.7). Reasons for revision were aseptic loosening (55%), pain/stiffness (27%), malrotation (9%), and instability (9%) in the MI TKA group and aseptic loosening (53%), instability (15%), pain/stiffness (8%), malrotation (8%), combined malrotation and instability (8%), and polyethylene wear/osteolysis (8%) in the traditional TKA group. These data suggest that MI TKA may be a risk factor for early revision.

Estrogen withdrawal following surgical ovariectomy was recently shown to mitigate particle-induced osteolysis in the murine calvarial model. Currently, we hypothesize that estrogen receptors (ERs) were involved in this paradoxical phenomenon. To test this hypothesis, we first evaluated polyethylene (PE) particle-induced osteolysis in the murine calvarial model, using wild type (WT) C57BL6J female mice, ERα deficient (ERαKO) mice, and WT mice either treated with 17β-estradiol (E2) or with the ER pan-antagonist ICI 182,780. According to micro-CT and histomorphometry, we showed that bone resorption was consistently altered in both ERαKO and ICI 182,780 treated mice as compared to WT and E2 groups. Then, we demonstrated that ER disruption consistently decreased both PE and polymethylmethacrylate (PMMA) particle-induced production of TNF-α by murine macrophages in vitro. Similar results were obtained following ER blockade using ICI 182,780 in RAW 264.7 and WT macrophages. ER disruption and pre treatment with ICI 182,780 resulted in a consistent down-regulation of particle-induced TNF-α mRNA expression relative to WT macrophages or untreated RAW cells. These results indicate that the response to wear particles involves estrogen receptors in female mice, as part of macrophage activation. Estrogen receptors may be considered as a future therapeutic target for particle-induced osteolysis.

This symposium is composed of selected papers delivered at the Fall 2011 Closed Meeting of The Hip Society in New Albany, OH, USA, and the Open Scientific Meeting of The Hip Society on Specialty Day at the 2012 Annual Meeting of the American Academy of Orthopaedic Surgeons in San Francisco, CA, USA. These meetings focused on current basic and clinical research related to novel biomaterials and alternative bearing surfaces, outcome studies on different surgical techniques and prosthesis designs for primary and revision hip arthroplasty, patient characteristics that may influence clinical outcome, and hip-preserving procedures. Metal-on-metal (MOM) hip articulations continue to undergo close scrutiny. Indeed, a recent FDA panel meeting was held to discuss pertinent scientific and clinical aspects related to this articulation. The present Hip Society symposium highlights several important studies that address topics such as the interpretation of metal ion levels after MOM hip arthroplasty and outcome studies on MOM total and resurfacing hip arthroplasty. Whereas some MOM bearings appear to be functioning quite well, others have been withdrawn from the market. Ongoing clinical surveillance, including periodic analysis of metal ion levels and imaging studies using advanced metal suppression techniques, will shed more light on the future of this bearing couple. Acetabular components containing crosslinked polyethylene (XLPE) continue to perform well in the intermediate term. Coupled with a metal or ceramic femoral head, XLPE now is the material of choice for the acetabular side. Larger femoral heads are being used with XLPE to obtain a more stable articulation, decreasing the dislocation rate substantially. Furthermore, patient activity appears to decrease with age, thus giving the possibility of increased longevity of currently implanted XLPE liners. However, overly thin polyethylene liners and suboptimal cup position are still discouraged because of the possibility of fracture of the plastic. Which patient characteristics increase the complication rate after THA? Recent evidence implicates smoking and excessive alcohol use as potential risk factors for early failure. Dislocation is also increased in patients with neurologic disorders and in complex revision cases. So-called minimally invasive surgical approaches have also garnered much recent attention. However, it appears no one surgical approach leads to a better outcome in experienced hands. Revision surgery on the femoral side often presents great challenges due to deficient bone stock and soft tissue compromise. Recent intermediate-term studies have shown modular tapered stems can have a satisfactory outcome in these difficult situations. Longer-term studies are needed to compare clinical outcomes with monoblock revision stems. This symposium highlights some of the important basic and clinical research reported by members of The Hip Society and serves an educational purpose for surgeons undertaking surgical procedures of the hip. The studies reported in this symposium have all undergone rigorous peer review. The Hip Society is pleased to present this information to help improve patient outcomes and stimulate ongoing research in this area. Fig. 1 Stuart B. Goodman MD, PhD is shown.

The generation of wear debris is an inevitable result of normal usage of joint replacements. Wear debris particles stimulate local and systemic biological reactions resulting in chronic inflammation, periprosthetic bone destruction, and eventually, implant loosening and revision surgery. The latter may be indicated in up to 15% patients in the decade following the arthroplasty using conventional polyethylene. Macrophages play multiple roles in both inflammation and in maintaining tissue homeostasis. As sentinels of the innate immune system, they are central to the initiation of this inflammatory cascade, characterized by the release of pro-inflammatory and pro-osteoclastic factors. Similar to the response to pathogens, wear particles elicit a macrophage response, based on the unique properties of the cells belonging to this lineage, including sensing, chemotaxis, phagocytosis, and adaptive stimulation. The biological processes involved are complex, redundant, both local and systemic, and highly adaptive. Cells of the monocyte/macrophage lineage are implicated in this phenomenon, ultimately resulting in differentiation and activation of bone resorbing osteoclasts. Simultaneously, other distinct macrophage populations inhibit inflammation and protect the bone-implant interface from osteolysis. Here, the current knowledge about the physiology of monocyte/macrophage lineage cells is reviewed. In addition, the pattern and consequences of their interaction with wear debris and the recent developments in this field are presented.

Mesenchymal stromal cell (MSCs) are key cellular components for site-specific tissue regeneration. The chemokine stromal derived factor 1 alpha (SDF-1α) is known to attract stem cells via the C-X-C chemokine receptor-4 (CXCR4) receptor. The aim of the study was to develop a model for stem cell attraction using SDF-1α overexpressing fat tissue grafts. Murine MSCs were lentiviral transduced to express the genes for enhanced green fluorescent protein, firefly luciferace, and human CXCR4 (hCXCR4). Murine fat tissue was adenoviral transduced to express SDF-1α and red fluorescent protein transgenes. MSCs were cultured on transwells with SDF-1α containing supernatants from transduced fat tissue. The numbers of migrated MSCs in four groups (with hCXCR4 positive (+) or hCXCR4 negative (−) MSCs with or without SDF-1α containing supernatant) were investigated. After 36 h of culture, 9025 ± 925 cells migrated through the membrane of the transwells in group 1 (CXCR4+/SDF-1α+), 4817 ± 940 cells in group 2 (CXCR4-/SDF-1α+), 2050 ± 766 cells in group 3 (CXCR4+/SDF-1α−), and 2108 ± 426 cells in group 4 (CXCR4-/SDF-1α-). Both, the presence of SDF-1α and the expression of hCXCR4 significantly increased the migration rates (p < 0.0001). MSCs overexpressing the CXCR4 receptor by lentiviral transduction are highly attracted by medium from SDF-1α expressing fat tissue in vitro. Thus, SDF-1α activated tissue grafts may be a strategy to enhance site-specific musculoskeletal tissue regeneration. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013.

Understanding how relevant cell types respond to wear particles will reveal new avenues for treating osteolysis following joint replacements. In this study, we investigate the effects of ultrahigh molecular weight polyethylene (UHMWPE) particles on preosteoblast migration and function. We infused UHMWPE particles or saline into the left femur of mice and injected luciferase-expressing preosteoblasts (MC3T3 cells) into each left ventricle. Bioluminescence imaging (BLI) confirmed systemic administration of MC3T3 cells. BLI throughout the 28-day experiment showed greater MC3T3 migration to the site of particle infusion than to the site of saline infusion, with significant differences on days 0, 4, and 6 (p≤0.055). Immunostaining revealed a greater number of osteoblasts and osteoclasts in the particle-infused femora, indicating greater bone turnover. The bone mineralization of the particle-infused femora increased significantly when compared to saline-infused femora (an increase of 146.4±27.9 vs. 12.8±8.7 mg/mL, p=0.008). These results show that infused preosteoblasts can migrate to the site of wear particles. Additionally, as the migrated cells were associated with increased bone mineralization in spite of the presence of particles, increasing osteoblast recruitment is a potential strategy for combating bone loss due to increased osteoclast/macrophage number and decreased osteoblast function.

This CORR Insights™ is a commentary on the article "Do Patients Lose Weight After Joint Arthroplasty Surgery? A Systematic Review" by Inacio and colleagues available at DOI 10.1007/s11999-012-2537-7 .

Numerous studies provide detailed insight into the triggering and amplification mechanisms of the inflammatory response associated with prosthetic wear particles, promoting final dominance of bone resorption over bone formation in multiple bone multicellular units around an implant. In fact, inflammation is a highly regulated process tightly linked to simultaneous stimulation of tissue protective and regenerative mechanisms in order to prevent collateral damage of periprosthetic tissues. A variety of cytokines, chemokines, hormones and specific cell populations, including macrophages, dendritic and stem cells, attempt to balance tissue architecture and minimize inflammation. Based on this fact, we postulate that the local tissue homeostatic mechanisms more effectively regulate the pro-inflammatory/pro-osteolytic cells/pathways in patients with none/mild periprosthetic osteolysis (PPOL) than in patients with severe PPOL. In this line of thinking, ‘particle disease theory’ can be understood, at least partially, in terms of the failure of local tissue homeostatic mechanisms. As a result, we envision focusing current research on homeostatic mechanisms in addition to traditional efforts to elucidate details of pro-inflammatory/pro-osteolytic pathways. We believe this approach could open new avenues for research and potential therapeutic strategies.

BACKGROUND: Determinants of the duration of opioid use after surgery have not been reported. We hypothesized that both preoperative psychological distress and substance abuse would predict more prolonged opioid use after surgery. METHODS: Between January 2007 and April 2009, a prospective, longitudinal inception cohort study enrolled 109 of 134 consecutively approached patients undergoing mastectomy, lumpectomy, thoracotomy, total knee replacement, or total hip replacement. We measured preoperative psychological distress and substance use, and then measured the daily use of opioids until patients reported the cessation of both opioid consumption and pain. The primary end point was time to opioid cessation. All analyses were controlled for the type of surgery done. RESULTS: Overall, 6% of patients continued on new opioids 150 days after surgery. Preoperative prescribed opioid use, depressive symptoms, and increased self-perceived risk of addiction were each independently associated with more prolonged opioid use. Preoperative prescribed opioid use was associated with a 73% (95% confidence interval [CI] 0.51%–87%) reduction in the rate of opioid cessation after surgery (P 0.0009). Additionally, each 1-point increase (on a 4-point scale) of self-perceived risk of addiction was associated with a 53% (95% CI 23%–71%) reduction in the rate of opioid cessation (P 0.003). Independent of preoperative opioid use and self-perceived risk of addiction, each 10-point increase on a preoperative Beck Depression Inventory II was associated with a 42% (95% CI 18%–58%) reduction in the rate of opioid cessation (P 0.002). The variance in the duration of postoperative opioid use was better predicted by preoperative prescribed opioid use, self-perceived risk of addiction, and depressive symptoms than postoperative pain duration or severity. CONCLUSIONS: Preoperative factors, including legitimate prescribed opioid use, self-perceived risk of addiction, and depressive symptoms each independently predicted more prolonged opioid use after surgery. Each of these factors was a better predictor of prolonged opioid use than postoperative pain duration or severity. (Anesth Analg 2012;115:694–702)

Currently, younger, more active patients are being offered total joint replacement (TJR) for end-stage arthritic disorders. Despite improved durability of TJRs, particle-associated wear of the bearing surfaces continues to be associated with particulate debris, which can activate monocyte/macrophages. Activated macrophages then produce pro-inflammatory factors and cytokines that induce an inflammatory reaction that activates osteoclasts leading to bone breakdown and aseptic loosening. We hypothesized that activated macrophages in tissues harvested from revised joint replacements predominantly express an M1 pro-inflammatory phenotype due to wear-particle-associated cell activation, rather than an M2 anti-inflammatory phenotype. We further questioned whether it is possible to convert uncommitted monocyte/macrophages to an M2 phenotype by the addition of interleukin-4 (IL-4), or whether it is necessary to first pass through an M1 intermediate stage. Retrieved periprosthetic tissues demonstrated increased M1/M2 macrophage ratios compared to non-operated osteoarthritic synovial tissues, using immunohistochemical staining and Western blotting. Uncommitted monocyte/macrophages with/without polymethyl-methacrylate particles were transformed to an M2 phenotype by IL-4 more efficiently when the cells were first passed through an M1 phenotype by exposure to endotoxin. Wear particles induce a pro-inflammatory microenvironment that facilitates osteolysis; these events may potentially be modulated favorably by exposure to IL-4.

The reconstruction of major acetabular bone defects during revision, conversion, and primary total hip arthroplasties (THAs) is challenging. We reviewed a consecutive series of 168 THAs (108 revisions, 8 conversions, and 52 primary THAs) performed by 1 surgeon (S.B.G.) between 1997 and 2008 using impaction bone grafting for acetabular reconstruction. Autograft, cancellous allograft croutons, and demineralized bone matrix were used to fill bone defects as needed. The acetabular bone deficiency was classified according to the American Academy of Orthopaedic Surgeons: type I, segmental deficiency with significant rim defect; type II, cavitary defects medially or posteriorly; type III, combined cavitary and segmental deficiency; type IV, pelvic discontinuity; and type V, arthrodesis. According to this method, 56 hips had type I, 31 hips had type II, 48 hips had type III, and 27 hips had type IV deficiencies. Of the 168 patients, 19 subsequently died of causes unrelated to the THA, and 11 were lost to follow-up. All patients had at least 2 years of follow-up. Average Harris Hip Score improved from 45.5±17.9 preoperatively to 81.1±16.5 postoperatively ( P P P

Total joint replacements are one of the most commonly performed orthopaedic procedures worldwide, with over 700,000 surgeries performed annually in the US to treat arthritic conditions of the hip and knee. One of the major complications of total joint replacement is implant wear and osteolysis, a process that involves continuous shedding of micronand submicron-sized particles from implant components. Implant particles elicit cascades of inflammatory, osteolytic, and granulomatous reactions from macrophages, osteoclasts, and fibroblasts, causing the prosthesis to become unstable. Since the mid 1990s, in vitro studies have shown that wear debris particles inhibit the osteogenic function of osteoblasts and osteoprogenitor cells of human and rodent species. Osteolysis and implant loosening involve not only increased bone resorption by osteoclasts and inflammatory cells, but also reduced bone formation by osteoblasts and their progenitors. This disruption of proliferation, differentiation, function, and survival of osteoblasts prevents the implant from properly integrating with surrounding bone. The inhibitory effects of implant wear debris on osteoblasts and osteoprogenitors have been demonstrated using particles of metallic (titanium, cobalt chrome), polymeric (polyethylene, PMMA), and ceramic (alumina, zirconia) implants. Human and rodent primary osteoblasts and osteoblast cell lines, such as MG-63 cells, treated with titanium and polyethylene particles in culture, uniformly show reduced type I collagen synthesis with evidence of particle phagocytosis and morphological changes consistent with cell injury and cytoskeletal disorganization on microscopy. Selected studies also show that particles impair osteoblast viability, proliferation, adhesion, extracellular matrix production, and osteogenic protein expression (e.g., alkaline phosphatase). Implant particles uniformly stimulate expression of NF-κB and IL-6, IL-8, PGE2, RANKL, M-CSF, and MCP-1, pro-inflammatory factors known to recruit monocyte-macrophages or induce osteoclast differentiation and activity. These studies also indicate that the effect of particles on osteoblasts depends on particle size and composition and the maturational state of the cell. Metal implants such as cobalt chromium and titanium alloys pose an additional risk of metal ion toxicity. Wear debris particles also inhibit the osteogenic activity of osteoprogenitors and marrow stromal cells (MSCs). Human bone marrow-derived MSCs exposed to titanium particles exhibit reduced proliferation, type I collagen expression, viability, and matrix mineralization with evidence of particle phagocytosis and structural and biochemical changes indicative of

The host response to biomaterials has been studied for decades. Largely, the interaction of host immune cells, macrophages in particular, with implanted materials has been considered to be a precursor to granulation tissue formation, the classic foreign body reaction, and eventual encapsulation with associated negative impacts upon device functionality. However, more recently, it has been shown that macrophages, depending upon context dependent polarization profiles, are capable of affecting both detrimental and beneficial outcomes in a number of disease processes and in tissue remodeling following injury. Herein, the diverse roles played by macrophages in these processes are discussed in addition to the potential manipulation of macrophage effector mechanisms as a strategy for promoting site-appropriate and constructive tissue remodeling as opposed to deleterious persistent inflammation and scar tissue formation.

Total hip arthoplasty (THA) is the most effective and safest method for treating severe degenerative, post-traumatic and other diseases of the hip joint. It is estimated that more than 1,000,000 THAs are performed each year globally. The incidence of primary THA increased in the period 1990 to 2002 in the USA from 47/100,000 to 69/100,000 (Kurtz et al. 2007). A similar study in Denmark reported an increased rate of THAs from 101/100,000 to 131/100,000 during the period 1996 to 2002 (Pedersen et al. 2005). More importantly, modelled future projections expect further increase in the need for THAs. It is believed that THA can reliably relieve pain and improve function in the majority of patients for a period of 15 to 20 years or more postoperatively. On this basis, with the extension of THAs to a younger and generally more active population, the expected time of service of THAs would be insufficient and the number of revision surgeries would therefore increase during this time. The Kaplan-Meier ten-year revision-free survival estimates for younger patients range from 72% (95%CI: 67-76) in Finland to 86% (95%CI: 84,5-88,2) in Sweden (Corbett et al. 2010). Hence, 14% to 28% of such patients on average did not achieve a 10-year THA functioning without revision. The main reason for late failure of THA is aseptic loosening accompanied by osteolysis followed by infection and instability of the THA that compromise more the early postoperative

Decreasing periprosthetic osteolysis due to wear particles is a current challenge and an on-going research endeavor to prolong the longevity of joint replacements. The aim of this chapter is to provide the reader keys to the understanding of how the immune system interacts with metallic and non metallic wear particles and other byproducts from joint replacements. The local and systemic immune system is involved in a complex network of chemokines, cytokines, and different cell types which in the end leads to inflammation and a foreign body reaction.

Both micromotion and particulate debris have been implicated in the process of aseptic loosening of joint arthroplasties and the failure of bone ingrowth into porous coated prostheses. In the present study, we compare the histological and histomorphometric results of tissue ingrowth into titanium chambers in the presence of interfacial micromotion versus phagocytosable particles of two polymers used in orthopedic surgery. The micromotion chamber, having a 1 × 1 × 5 mm transverse canal for tissue ingrowth was implanted into the proximal right tibia of five mature male New Zealand white rabbits. In the first series, the chambers were manipulated at 40 cycles per day (cpd) at 1 Hz, using an amplitude of 0.5 mm. The tissue within the chamber was harvested after 3 weeks. In the following series, fabricated particles of bone cement or highdensity polyethylene (HDPE) were mixed with the carrier, 1% sodium hyaluronate (Healon) to obtain a concentration of 108 particles/mL; this solution was implanted in the canal of the chamber but micromotion was not instituted. Histological sections from control, nonmoved chambers, or those implanted with the carrier Healon alone contained extensive trabecular and woven bone embedded in a fibrovascular stroma. The application of 40 cpd resulted in less formation of bone and more fibrous tissue within the chamber. The sections containing particles of bone cement were infiltrated by numerous foamy, mononuclear, and multinuclear histiocytes. HDPE particles were associated with more fibrosis and a less aggressive foreign body response compared to cement particles. Chambers manipulated at 40 cpd and those containing cement or HDPE particles contained less bone compared to nonmoved chambers or those containing Healon alone. Despite evoking different histological reactions, the presence of micromotion or polymer particles appears to inhibit the formation of bone in this experimental model. © 1994 John Wiley & Sons, Inc.

The immune and coagulation systems are both implicated in the pathogenesis of rheumatoid arthritis (RA). Plasma carboxypeptidase B (CPB), which is activated by the thrombin/thrombomodulin complex, plays a procoagulant role during fibrin clot formation. However, an antiinflammatory role for CPB is suggested by the recent observation that CPB can cleave proinflammatory mediators, such as C5a, bradykinin, and osteopontin. Here, we show that CPB plays a central role in downregulating C5a-mediated inflammatory responses in autoimmune arthritis. CPB deficiency exacerbated inflammatory arthritis in a mouse model of RA, and cleavage of C5a by CPB suppressed the ability of C5a to recruit immune cells in vivo. In human patients with RA, genotyping of nonsynonymous SNPs in the CPB-encoding gene revealed that the allele encoding a CPB variant with longer half-life was associated with a lower risk of developing radiographically severe RA. Functionally, this CPB variant was more effective at abrogating the proinflammatory properties of C5a. Additionally, expression of both CPB and C5a in synovial fluid was higher in patients with RA than in those with osteoarthritis. These findings suggest that CPB plays a critical role in dampening local, C5a-mediated inflammation and represents a molecular link between inflammation and coagulation in autoimmune arthritis.

With the institution of quality-assurance parameters in health care, physicians must accurately measure and report the true baseline rates of adverse events (AEs) after complex surgical interventions. To better quantify the risk of AEs for revision total hip arthroplasty (THA), we divided a cohort of 306 patients (322 procedures) into age groups: group I (

The inflammatory response to prosthetic implant-derived wear particles is the primary cause of bone loss and aseptic loosening of implants, but the mechanisms by which macrophages recognize and respond to particles remain unknown. Studies of innate immunity demonstrate that Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPS). All TLRs signal through myeloid differentiation factor 88 (MyD88), except TLR3 which signals through TIR domain containing adapter inducing interferon-beta (TRIF), and TLR4 which signals through both MyD88 and TRIF. We hypothesized that wear-debris particles may act as PAMPs/DAMPs and activate macrophages via TLRs. To test this hypothesis, we first demonstrated that inhibition of MyD88 decreases polymethylmethacrylate (PMMA) particle-induced production of TNF-α in RAW 264.7 macrophages. Next we compared particle-induced production of TNF-α among MyD88 knockout (MyD88(-/-)), TRIF knockout (TRIF(-/-)), and wild type (WT) murine macrophages. Relative to WT, disruption of MyD88 signaling diminished, and disruption of TRIF amplified the particle-induced production of TNF-α. Gene expression data indicated that this latter increase in TNF-α was due to a compensatory increase in expression of MyD88 associated components of the TLR pathway. Finally, using an in vivo model, MyD88(-/-) mice developed less particle-induced osteolysis than WT mice. These results indicate that the response to PMMA particles is partly dependent on MyD88, presumably as part of TLR signaling; MyD88 may represent a therapeutic target for prevention of wear debris-induced periprosthetic osteolysis.

Purpose: To evaluate two magnetic resonance imaging (MRI) techniques, slice encoding for metal artifact correction (SEMAC) and multiacquisition variable-resonance image combination (MAVRIC), for their ability to correct for artifacts in postoperative knees with metal. Materials and Methods: A total of 25 knees were imaged in this study. Fourteen total knee replacements (TKRs) in volunteers were scanned with SEMAC, MAVRIC, and 2D fast spin-echo (FSE) to measure artifact extent and implant rotation. The ability of the sequences to measure implant rotation and dimensions was compared in a TKR knee model. Eleven patients with a variety of metallic hardware were imaged with SEMAC and FSE to compare artifact extent and subsequent patient management was recorded. Results: SEMAC and MAVRIC significantly reduced artifact extent compared to FSE (P < 0.0001) and were similar to each other (P = 0.58), allowing accurate measurement of implant dimensions and rotation. The TKRs were properly aligned in the volunteers. Clinical imaging with SEMAC in symptomatic knees significantly reduced artifact (P < 0.05) and showed findings that were on the majority confirmed by subsequent noninvasive or invasive patient studies. Conclusion: SEMAC and MAVRIC correct for metal artifact, noninvasively providing high-resolution images with superb bone and soft tissue contrast. J. Magn. Reson. Imaging 2011;33:1121–1127. © 2011 Wiley-Liss, Inc.

Background Placental dysfunction underlies numerous complications of pregnancy. A major obstacle to understanding the roles of potential mediators of placental pathology has been the absence of suitable methods for tissue-specific gene manipulation and sensitive assays for studying gene functions in the placentas of intact animals. We describe a sensitive and noninvasive method of repetitively tracking placenta-specific gene expression throughout pregnancy using lentivirus-mediated transduction of optical reporter genes in mouse blastocysts. Methodology/Principal Findings Zona-free blastocysts were incubated with lentivirus expressing firefly luciferase (Fluc) and Tomato fluorescent fusion protein for trophectoderm-specific infection and transplanted into day 3 pseudopregnant recipients (GD3). Animals were examined for Fluc expression by live bioluminescence imaging (BLI) at different points during pregnancy, and the placentas were examined for tomato expression in different cell types on GD18. In another set of experiments, blastocysts with maximum photon fluxes in the range of 2.0E+4 to 6.0E+4 p/s/cm2/sr were transferred. Fluc expression was detectable in all surrogate dams by day 5 of pregnancy by live imaging, and the signal increased dramatically thereafter each day until GD12, reaching a peak at GD16 and maintaining that level through GD18. All of the placentas, but none of the fetuses, analyzed on GD18 by BLI showed different degrees of Fluc expression. However, only placentas of dams transferred with selected blastocysts showed uniform photon distribution with no significant variability of photon intensity among placentas of the same litter. Tomato expression in the placentas was limited to only trophoblast cell lineages. Conclusions/Significance These results, for the first time, demonstrate the feasibility of selecting lentivirally-transduced blastocysts for uniform gene expression in all placentas of the same litter and early detection and quantitative analysis of gene expression throughout pregnancy by live BLI. This method may be useful for a wide range of applications involving trophoblast-specific gene manipulations in utero.

The interfacial membrane harvested from failed joint replacements contains particulate debris from the materials used for the implant. To define the tissue response to particulate titanium alloy and hydroxyapatite (HA) alone, 16 mature New Zealand white rabbits were divided into 2 groups of 8 rabbits. Using sterile technique, a drill hole was placed anteromedially in the tibia, 1 cm distal to the knee joint bilaterally. The marrow was scooped out and 0.25 mg of either titanium alloy particles or HA particles were inserted in the right tibia. The titanium alloy particles had a diameter averaging 4.0 ± 4.4 μm (mean ± standard deviation) and an aspect ratio (the ratio of the maximum length divided by the maximum width) of 1.84. The HA particles had a diameter of 4.4 ± 3.3 μm and an aspect ratio of 1.76. The left leg was prepared in a similar fashion, but no biomaterial was implanted. The animals were killed after 16 wk. The harvested tibiae were processed with decalcification and the plastic-embedded sections were subjected to histomorphological analysis. Black titanium alloy particles were present within the bone marrow fat between haematopoietic cells, and within scattered macrophages. The surrounding bone appeared to be unaffected. Within the spongiosa, the HA particles were surrounded by small numbers of mononuclear histiocytes or encased within a shell of new appositional bone. Where HA deposits were exposed to the endosteal aspect of bone, there was scalloping of the surface of the HA in a pattern suggestive of resorption or dissolution of the HA particles. Haematopoietic activity was present at the margins of the surgically operated zone and the HA particles were intermingled with haematopoietic cells. Intracortical deposits of HA were totally encased by layers of appositional lamellar bone. The findings in this in vivo study contrast with the florid foreign body and chronic inflammatory reaction associated with particles of poly(methyl methacrylate) and polyethylene in similar experimental studies, and in failed arthroplasties in humans.

Fourteen mature New Zealand white female rabbits had a unilateral cemented, stemmed, titanium, condylar-type tibial hemiarthroplasty, using an anteromedial arthrotomy of the right knee. The articular cartilage and minimal bone were resected. There were two prosthetic groups of seven animals each: a well-fixed, non-loose group and a loose group. In the non-loose group, the implant was inserted into the cement bed and axially compressed until the PMMA had cured. In the loose group, the same volume of cement was allowed to cure on the implant ex vivo; the prosthesis was then implanted to ensure that it was loose fitting. Radiographs were performed at zero and 3 months and graded for new lucent lines. Histological analysis was performed using undecalcified coronal sections, surface stained with toluidine blue with the prosthesis in situ, and the cement mantle preserved. Back-scattered electron microscopy was also performed. The mean cumulative grading of new lucent lines was 0.3 +/- 0.1 for the non-loose group and 2.2 +/- 0.4 for the loose group (P0.005). Non-loose prostheses were surrounded by a thin fibrous membrane or bone. Loose prostheses were surrounded by a thicker, fibrous tissue layer, containing histiocytes and giant cells which were more prevalent around cement particles, especially near the prosthetic tip. These findings parallel the histology found at cemented prosthetic interfaces in humans. The results of this study suggest that the fibrohistiocytic membrane commonly found around loose cemented implants may be the result of, rather than the cause of, the loosening process.

In 1892, J.L. Wolff believed that bone was a dynamic organ that responded to the biomechanical environment. Research has shown that mechanical stimulation can have a profound effect on the differentiation and development of mesenchymal tissues. It would appear that a 'window' of mechanical strain exists which may facilitate or discourage the accretion of bone. With respect to processes such as fracture healing and ingrowth of bone into porous coated prostheses, it may be possible to modulate the mechanical environment with the application of well-defined, exogenous loads in order to promote a more favourable outcome.