Pathogenesis Of Aseptic Loosening Research Articles

Macrophages in aseptic loosening: Characteristics, functions, and mechanisms.

Aseptic loosening (AL) is the most common complication of total joint arthroplasty (TJA). Both local inflammatory response and subsequent osteolysis around the prosthesis are the fundamental causes of disease pathology. As the earliest change of cell behavior, polarizations of macrophages play an essential role in the pathogenesis of AL, including regulating inflammatory responses and related pathological bone remodeling. The direction of macrophage polarization is closely dependent on the microenvironment of the periprosthetic tissue. When the classically activated macrophages (M1) are characterized by the augmented ability to produce proinflammatory cytokines, the primary functions of alternatively activated macrophages (M2) are related to inflammatory relief and tissue repair. Yet, both M1 macrophages and M2 macrophages are involved in the occurrence and development of AL, and a comprehensive understanding of polarized behaviors and inducing factors would help in identifying specific therapies. In recent years, studies have witnessed novel discoveries regarding the role of macrophages in AL pathology, the shifts between polarized phenotype during disease progression, as well as local mediators and signaling pathways responsible for regulations in macrophages and subsequent osteoclasts (OCs). In this review, we summarize recent progress on macrophage polarization and related mechanisms during the development of AL and discuss new findings and concepts in the context of existing work.

Vitamin E-added Highly Cross-Linked Polyethylene Decreases the Risk of Osteolysis in an In Vivo Arthroplasty Model.

Introduction Aseptic loosening is one of the most important complications of arthroplasty surgery. It is known that immune response against particles plays role in the pathogenesis of aseptic loosening. Polyethylene (PE) has an important place in these particles. There are limited in vivo studies examining aseptic loosening caused by PE residues. Objective The aim of the present study is to evaluate the aseptic loosening created by highly cross-linked PE (HXLPE) and vitamin E-added PE particlesin an in vivo knee prosthesis model. Materials and methods Thirty-nine male Sprague-Dawley rats, which were randomized into three groups, were included in the study. After surgical exposure of knee joints of rats, femoral intramedullary canals were drilled and instilled with isolated saline solution and saline solution that contained standard PE or vitamin E-added PE particles according to their groups. Afterwards, a titanium implant was placed on the femoral articular surface of each animal. Rats received intraarticular injections weekly of the same solution, which was initially instilled into their femoral canal. The rats were sacrificed at the end of the third week and then underwentradiological and histopathological evaluations. Result In histopathological evaluation, periprosthetic membrane formation, inflammatory cell change, and cellular damage of cartilage and bone tissue around the implant were assessed. There was a statistically lesser amount of cellular damage and periprosthetic membrane formation in the vitamin-E/HXLPE group compared to the HXLPE group (p=0.04, p=0.001). No significant difference was found between the PE groups with respect to inflammatory cells (p=0.715). Conclusions HXLPE caused more significant osteolysis compared to VE-HXLPE. Antioxidants in PE could provide a reduction in osteolysis and aseptic loosening.

CircRNA expression pattern and ceRNA network in the pathogenesis of aseptic loosening after total hip arthroplasty.

Increasing evidence has demonstrated that circular RNA (circRNA) exerts important function in the pathogenesis of some diseases. While, the contributions of circRNAs to aseptic loosening after total hip arthroplasty (THA) remain largely unknown. Our research is to explore the differentially expressed circRNAs (DEcircRNAs) and elucidate complex regulated mechanism of circRNAs in aseptic loosening. The DEcircRNAs were identified by RNA sequencing (RNA-seq) analysis. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was adopted to corroborate these DEcircRNAs. The potential function of circRNAs in aseptic loosening tissue was identified by competing endogenous RNA (ceRNA) analysis. Enrichment analysis was performed for target mRNAs and host genes of the DEcircRNAs by Gene Oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). 257 DEcircRNAs were obtained from RNA-seq results. Following the RT-qPCR corroboration, 6 circRNAs (hsa_circ_0007482, hsa_circ_0005232, hsa_circ_0000994, hsa_circ_0000690, hsa_circ_0058092 and hsa_circ_0004496) were selected for further analysis. By circRNA-miRNA and miRNA-mRNA prediction, 6 circRNAs, 138 miRNAs and 1667 mRNAs were identified. Then, circRNA-miRNA-mRNA network was established. The result of GO and KEGG enrichment analysis suggested that the circRNAs were related with some biological functions and pathways of aseptic loosening. A novel pathogenesis and treatment strategy about aseptic loosening after THA was revealed from our study of circRNA-miRNA-mRNA network.

A Modified Murine Calvarial Osteolysis Model Exposed to Ti Particles in Aseptic Loosening.

Aim To investigate the different effects on osteolysis between commercial pure Ti particles and TiAl6V4 particles obtained from prosthesis of patients with aseptic loosening. Method Scanning electron microscope, energy dispersive X-ray spectrometry, and X-ray diffraction were used for the size test, chemical composition test, and phase analysis of two kinds of Ti particles. Microcomputed tomography (micro-CT) and 3-dimensional reconstruction analysis were applied to analyze the bone loss quantitatively and radiologically. Hematoxylin-eosin (HE) staining and tartrate-resistant acid phosphatase (TRAP) staining were used to assess the histologic difference. Result TiAl6V4 particles were constituted by FeO, Al45V7, and Al3Ti while pure Ti particles were constituted by Ti, Ti3O, and C4H7NO3. Similar particle size of nanoscale was detected of two Ti particles. A TiAl6V4 osteolysis model had more severe bone loss when scanned with micro-CT and assessed by quantitative analysis. TiAl6V4 also presented deeper and wider calvarial bone loss in HE staining and more activated osteoclasts in TRAP staining. Conclusion A mouse calvarial model is the most effective animal model for the primary in vivo research of aseptic loosening. Compared with commercial Ti particles, TiAl6V4 particles derived from prosthesis of an aseptic loosening patient had more severe bone loss and more activated osteoclast, which was more consistent with pathogenesis of aseptic loosening in vivo, had high success rate of establishment of a model, and was more desired in animal modeling.

Autophagy Involvement in Aseptic Loosening of Arthroplasty Components.

➤ Aseptic loosening, the most common cause of arthroplasty component failure, is due to implant wear and subsequent release of biomaterial wear particles to the bone microenvironment, leading to a chronic inflammatory response.➤ Autophagy, a cell-cleaning process allowing the degradation of damaged material, can be upregulated in response to various stresses in which it acts primarily as a survival mechanism. In addition to the classic role of autophagy in the degradation pathway, autophagy can be involved in some secretion processes.➤ Autophagy seems to be triggered by the presence of wear debris in the 3 main cell types involved in aseptic loosening, i.e., osteocytes, osteoblasts, and macrophages.➤ Autophagy can mediate the secretion of proinflammatory cytokines such as interleukin (IL)-6 and IL-8 or the danger signal protein HMGB1 (high mobility group box 1). All of these proteins have been implicated in the pathogenesis of aseptic loosening.➤ Recent studies using animal models have demonstrated that autophagy inhibition can decrease the severity of osteolysis, suggesting that transient and local autophagy modulation could be a potential therapeutic option to prevent wear debris-induced osteolysis.

Particulate and ion forms of cobalt-chromium challenged preosteoblasts promote osteoclastogenesis and osteolysis in a murine model of prosthesis failure.

This study investigated the interactive behavior of the particulate and ion forms of cobalt-chromium (Co-Cr) alloy challenged preosteoblasts during the process of prosthetic implant loosening. Preosteoblasts were challenged with Co-Cr particles or Co(II) ions for 72 h, followed by the proliferation and PCR assays. For in vivo test, a titanium pin was implanted into proximal tibia of SCID mice to mimic knee replacement. Co-Cr particles or Co(II) ion challenged preosteoblasts (5 × 105 ) were intra-articularly injected into the implanted knee. The animals were sacrificed 5 weeks post-op, and the prosthetic knees were harvested for biomechanical pin-pullout testing, histological evaluations, and microCT assessment. In vitro study suggested that Co-Cr particles and Co(II) ions significantly suppressed the proliferation of preosteoblasts in a dose-dependent manner. RT-PCR data on the challenged cells indicated overexpression of receptor activator of nuclear factor kappa-B ligand (RANKL) and inhibited osteoprotegerin (OPG) gene expression. Introduction of the differently challenged preosteoblasts to the pin-implant mouse model resulted in reduced implant interfacial shear strength, thicker peri-implant soft-tissue formation, more TRAP+ cells, lower bone mineral density, and bone volume fraction. In conclusion, both Co-Cr particles and Co(II) ions interfered with the growth, maturation, and functions of preosteoblasts, and provides evidence that the metal ions as well play an important role in effecting preosteoblasts in the pathogenesis of aseptic loosening. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 187-194, 2019.

Nano-sized Al2O3 particle-induced autophagy reduces osteolysis in aseptic loosening of total hip arthroplasty by negative feedback regulation of RANKL expression in fibroblasts

Aseptic loosening is mainly caused by wear debris generated by friction that can increase the expression of receptor activation of nuclear factor (NF)-κB (RANKL). RANKL has been shown to support the differentiation and maturation of osteoclasts. Although autophagy is a key metabolic pathway for maintaining the metabolic homeostasis of cells, no study has determined whether autophagy induced by Al2O3 particles is involved in the pathogenesis of aseptic loosening. The aim of this study was to evaluate RANKL levels in patients experiencing aseptic loosening after total hip arthroplasty (THA) and hip osteoarthritis (hOA) and to consequently clarify the relationship between RANKL and LC3II expression. We determined the levels of RANKL and autophagy in fibroblasts treated with Al2O3 particles in vitro while using shBECN-1 interference lentivirus vectors to block the autophagy pathway and BECN-1 overexpression lentivirus vectors to promote autophagy. We established a novel rat model of femoral head replacement and analyzed the effects of Al2O3 particles on autophagy levels and RANKL expression in synovial tissues in vivo. The RANKL levels in the revision total hip arthroplasty (rTHA) group were higher than those in the hOA group. In patients with rTHA with a ceramic interface, LC3II expression was high, whereas RANKL expression was low. The in vitro results showed that Al2O3 particles promoted fibroblast autophagy in a time- and dose-dependent manner and that RANKL expression was negatively correlated with autophagy. The in vivo results further confirmed these findings. Al2O3 particles induced fibroblast autophagy, which reduced RANKL expression. Decreasing the autophagy level promoted osteolysis and aseptic prosthetic loosening, whereas increasing the autophagy level reversed this trend.

Strontium ranelate inhibits wear particle-induced aseptic loosening in mice.

The imbalance between bone formation and osteolysis plays a key role in the pathogenesis of aseptic loosening. Strontium ranelate (SR) can promote bone formation and inhibit osteolysis. The aim of this study was to explore the role and mechanism of SR in aseptic loosening induced by wear particles. Twenty wild-type (WT) female C57BL/6j mice and 20 sclerostin-/- female C57BL/6j mice were used in this study. Mice were randomly divided into four groups: WT control group, WT SR group, knockout (KO) control group, and KO SR group. We found that SR enhanced the secretion of osteocalcin (0.72±0.007 in WT control group, 0.98±0.010 in WT SR group, P=0.000), Runx2 (0.34±0.005 in WT control group, 0.47±0.010 in WT SR group, P=0.000), β-catenin (1.04±0.05 in WT control group, 1.22±0.02 in WT SR group, P=0.000), and osteoprotegerin (OPG) (0.59±0.03 in WT control group, 0.90±0.02 in WT SR group, P=0.000). SR significantly decreased the level of receptor activator for nuclear factor-κB ligand (RANKL) (1.78±0.08 in WT control group, 1.37±0.06 in WT SR group, P=0.000) and improved the protein ratio of OPG/RANKL, but these effects were not observed in sclerostin-/- mice. Our findings demonstrated that SR enhanced bone formation and inhibited bone resorption in a wear particle-mediated osteolysis model in wild-type mice, and this effect relied mainly on the down-regulation of sclerostin levels to ameliorate the inhibition of the canonical Wnt pathway.

Correlations between macrophage polarizing cytokines, inflammatory mediators, osteoclast activity, and toll-like receptors in tissues around aseptically loosened hip implants.

Aseptic loosening and osteolysis of joint replacements are driven by macrophage-mediated inflammatory reactions to implant-derived wear debris, but many aspects of these events remain poorly characterized. To better understand the relationships among inflammatory and chemotactic mediators, macrophage phenotype and polarizing cytokines, osteoclast activity, and Toll-like receptors (TLRs) in the pathogenesis of aseptic loosening, we determined how the relative expressions of these factors in the peri-implant tissues correlate to each other and to the life span of the implants using Pearson correlation. The expression of pro-inflammatory mediators and chemokines showed positive correlations among themselves, and with TLR4. Furthermore, M1-polarizing IFN-γ showed positive correlations with a number of pro-inflammatory and chemotactic mediators, whereas M2-polarizing IL-4 showed no such association. IL-8 expression significantly correlated with early time to revision. Similar trends were observed for TNF-α, IFN-γ, and CCL3, while the opposite was detected for IL-4. However, none of the inflammatory mediators correlated with the markers of osteoclast activity or the RANKL/OPG ratio. The results highlight the importance of the inflammatory mediators, IFN-γ and TLR4, in the pathogenesis of aseptic loosening; increased pro-inflammatory status was associated with early time to revision, whereas IL-4 correlated with longer implant survival. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 454-463, 2017.

The Role of TLR and Chemokine in Wear Particle-Induced Aseptic Loosening

Wear particle-induced periprosthetic osteolysis remains the principal cause of aseptic loosening of orthopaedic implants. Monocytes/macrophages phagocytose wear particles and release cytokines that induce inflammatory response. This response promotes osteoclast differentiation and osteolysis. The precise mechanisms by which wear particles are recognized and induce the accumulation of inflammatory cells in the periprosthetic tissue have not been fully elucidated. Recent studies have shown that toll-like receptors (TLRs) contribute to the cellular interaction with wear particles. Wear particles are recognized by monocytes/macrophages through TLRs coupled with the adaptor protein MyD88. After the initial interaction, wear particles induce both local and systemic migration of monocytes/macrophages to the periprosthetic region. The cellular migration is mediated through chemokines including interleukin-8, macrophage chemotactic protein-1, and macrophage inhibitory protein-1 in the periprosthetic tissues. Interfering with chemokine-receptor axis can inhibit cellular migration and inflammatory response. This paper highlights recent advances in TLR, and chemokine participated in the pathogenesis of aseptic loosening. A comprehensive understanding of the recognition and migration mechanism is critical to the development of measures that prevent wear particle-induced aseptic loosening of orthopaedic implants.

Pathways of macrophage apoptosis within the interface membrane in aseptic loosening of prostheses

Aseptic loosening is a major cause of failure of total hip arthroplasty (THA). Macrophage apoptosis in interface membrane has been proved to play an important role in the pathogenesis of aseptic loosening. The purpose of current study was to identify the apoptotic mechanism of macrophages in the interface membrane of aseptic loosening. We collected periprosthetic interface membrane from 23 patients undergoing the revision operations for aseptic loosening of hip joint prostheses. To serve as the control group, samples of capsule were collected from 18 patients undergoing the primary hip arthroplasties for osteoarthritis (OA). The ultrastructure of interface membrane was examined by transmission electron microscopy (TEM), and in situ apoptotic macrophage identification was performed by TUNEL staining. Furthermore, using immunohistochemical methods we investigated the expression of some apoptosis-related markers such as inducible nitric oxide synthase (iNOS), peroxynitrite (ONOO −), cleaved caspase-3/4/8/9, cytochrome c, glucose regulated protein 78 (GRP78), and growth arrest and DNA damage-inducible gene 153 (GADD153) in macrophages. These markers were regarded as apoptotic inducers or specific indicators of different apoptotic pathways such as death receptor pathway, mitochondrial pathway and endoplasmic reticulum (ER) stress pathway. TEM showed that a great deal of wear debris was phagocytosed by macrophages, which displayed morphological changes characteristic of apoptosis. The results of TUNEL staining demonstrated that there were more apoptotic macrophages in interface membrane. The expression levels of iNOS, ONOO −, cleaved caspase-3/4/8/9, cytochrome c, GRP78 and GADD153 in macrophages in interface membrane were significantly higher than those in the control samples ( p < 0.05). Our results suggest that death receptor pathway, mitochondria/cytochrosome c caspase-dependent pathway and ER stress pathway are involved in the process of macrophage apoptosis. A therapeutic target to modulate the apoptotic pathways in macrophages may be a strategy to prevent and treat aseptic loosening.

Substance P Stimulates Production of Interleukin 1 β and Tumor Necrosis Factor α in Fibroblasts From Hip Periprosthetic Membrane

Aseptic loosening remains the primary cause of failure in total joint arthroplasty. Substance P (SP)–immunoreactive nerve fibers have been detected in the pseudomembrane and pseudocapsular tissues of aseptic loose hip prostheses, suggesting that SP might be involved in the process of aseptic loosening. We isolated fibroblasts from periprosthetic membrane at the time of revision hip arthroplasty performed because of aseptic loosening. Fibroblasts were incubated in the presence of various concentrations of SP, and the levels of interleukin 1 β, and tumor necrosis factor α in the media were determined using enzyme-linked immunosorbent assay kit. We found that the levels of interleukin 1 β and tumor necrosis factor α increased in a time- and concentration-dependent manner. Our results suggested that SP might be involved in the pathogenesis of aseptic loosening.

Erythromycin inhibits wear debris-induced osteoclastogenesis by modulation of murine macrophage NF-κB activity

Activation of nuclear factor kappa B (NF-κB) signaling in response to cell stimulation by wear debris may be critical in the pathogenesis of aseptic loosening. Erythromycin (EM), a macrolide antibiotic, has been shown to effectively suppress some types of inflammatory reactions. In this study, we examined the effect of EM on wear debris-induced osteoclastic bone resorption in vitro. EM inhibited Ca + release from neonatal calvaria co-cultured with conditioned medium from mouse RAW264.7 macrophages activated by wear debris. Inhibition of Ca + release was associated with a decreased number of tartrate-resistant acid phosphatase (TRAP)-positive cells in cultured bones. To investigate the mechanism whereby EM inhibits bone-resorption, RAW cells were incubated with wear debris in the presence EM. Real time RT-CR analysis revealed that EM (5 μg/ml) significantly inhibited mRNA expression of NF-κB, cathepsin K (CPK), IL-1β and TNFα, but not RANK in RAW cells stimulated with wear debris. Furthermore, electrophoretic mobility-shift assay showed that EM (0.2 μg–5 μg/ml) could reduce DNA-binding activity of NF-κB in RAW cells stimulated with wear debris. The inhibition of inflammatory osteoclastogenesis by EM treatment was further confirmed by an osteoclast (OC) formation assay using primary cultures of mouse bone marrow progenitor cells stimulated with macrophage colony-stimulating factor and RANK ligand (RANKL). EM treatment (5 μg/ml) resulted in more than 70% reduction in multinucleated OC formation and 50% reduction of TRAP + cells by bone marrow progenitor cells. Our findings support that EM suppresses wear debris-induced osteoclastic bone resorption by, at least, down-regulation of NF-κB signaling pathway. It appears that EM represents a potential therapeutic candidate for the treatment and prevention of aseptic loosening.

The role of adsorbed endotoxin in particle-induced stimulation of cytokine release

Numerous in vitro models have demonstrated the capacity of wear particles to stimulate the release of soluble pro-inflammatory products with the ability to induce local bone resorption. Recent observations have demonstrated that binding of lipopolysaccharide (LPS) to particulate wear debris can significantly modulate the pattern of cell response in the in vitro models. These findings raise concerns over the possible role of LPS in the pathogenesis of aseptic loosening after total joint replacements, and also indicates the importance of controlling for possible confounding effects of LPS contamination in the in vitro models used to study the reactive nature of wear debris. Our studies were undertaken to rigorously analyze the effects of particle-associated LPS on cell responses and to assess the efficacy of different treatment protocols to inactivate LPS associated with different particulate materials. Particles of cobalt–chrome alloy, titanium–6-aluminum–4-vanadium, titanium nitride and silica were pretreated with LPS and exposed to multiple treatment protocols. When cells were treated with “as-received” particles prepared by washing in ethanol, small amounts of TNF-α, IL-1β, and IL-1α were detected. In contrast, all particle species pretreated with LPS produced marked increases in TNF-α, IL-1α, and IL-1β release, as well as upregulation of corresponding mRNA levels even after ethanol washing. Boiling the LPS-pretreated particles in 1% acetic acid or autoclaving and baking the particles also markedly reduced and in some instances abolished the effect of the LPS-pretreatment. This indicates that LPS binds to the surface of particles of diverse composition and that the bound LPS is biologically active. Treatment protocols to inactivate particle-associated LPS demonstrated significant differences in efficacy. When the most rigorous treatments were utilized, essentially all LPS activity could be eliminated. Particles treated with these methods retained some capacity to stimulate cytokine release, but activities were markedly reduced. These results provide further evidence indicating that LPS contamination of particulate materials can markedly enhance their biological activity. This potential confounding effect needs to be carefully monitored and controlled in the in vitro model systems used to evaluate wear particles. Furthermore, the presence of particle-associated endotoxin at the bone—implant interface in vivo could markedly enhance the adverse biological activity of particulate wear debris.

Effect of PMMA particles and movement on an implant interface in a canine model.

The pathogenesis of aseptic loosening of total joint prostheses is not clearly understood. Two features are associated with loosened prostheses, namely, particulate debris and movement of the implant. While numerous studies have evaluated the cellular response to particulate biomaterials, few have investigated the influence of movement of the implant on the biological response to particles. Our aim was therefore to test the hypothesis that excessive mechanical stimulation of the periprosthetic tissues induces an inflammatory response and that the addition of particulate biomaterials intensifies this. We allocated 66 adult Beagle dogs to four groups as follows: stable implants with (I) and without (II) particulate polymethylmethacrylate (PMMA) and moving implants with (III) and without (IV) particulate PMMA. They were then evaluated at 2, 4, 6, 12 and 24 weeks. The stable implants were well tolerated and a thin, fibrous membrane of connective tissue was observed. There was evidence of positive staining in some cells for interleukin-6 (IL-6). Addition of particulate PMMA around the stable implants resulted in an increase in the fibroblastic response and positive staining for IL-6 and tumour necrosis factor-alpha (TNF-alpha). By contrast, movement of the implant resulted in an immediate inflammatory response characterised by large numbers of histiocytes and cytokine staining for IL-1beta, TNF-alpha and IL-6. Introduction of particulate PMMA aggravated this response. Animals with particulate PMMA and movement of the implant have an intense inflammatory response associated with accelerated bone loss. Our results indicate that the initiation of the inflammatory response to biomaterial particles was much slower than that to gross mechanical instability. Furthermore, when there was both particulate debris and movement, there was an amplification of the adverse tissue response as evidenced by the presence of osteolysis and increases in the presence of inflammatory cells and their associated cytokines.

Cytokine and Eicosanoid Production by Cultured Human Monocytes Exposed to Titanium Particulate Debris.

: Phagocytosis of particulate wear debris from arthroplasties by macrophages induces an inflammatory response that has been linked to implant loosening and premature failure of artificial joints. Inflammatory mediators released by phagocytic macrophages such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and prostaglandin E(2) (PGE(2)) are believed to play a central role in the pathogenesis of aseptic loosening. The objective of this study was to characterize titanium alloy particulates that closely match wear debris found around joint arthroplasties and to study their effects on the biosynthesis of inflammatory mediators by cultured monocytes. Peripheral blood monocytes were isolated from healthy human volunteers. Monocytes were cultured in 96-well plates for 24 h, washed, and exposed to three concentrations of titanium particulates and controls from 18-24 h. Supernatants were assayed for TNF-alpha, IL-1beta, IL-6, and PGE(2) activity. Energy dispersive X-ray spectroscopy (EDX) verified the titanium alloy to be Ti6A14V. Scanning electron microscopy (SEM) analysis showed significant titanium particulate heterogeneity with approximately 95% of the particles <1 µm in diameter. SEM and EDX technology was useful in the characterization of the titanium particulates utilized for in vitro models of titanium-induced cytokine release by monocytes. Incubation of titanium particulates (in concentrations similar to those found around loosened prosthetic joints) with cultured monocytes significantly increased their production of TNF-alpha, IL-1beta, and PGE(2).

Total joint arthroplasty and the immune response

Total joint replacement arthroplasty has proved highly successful in themanagement of osteoarthritis and rheumatoid arthritis. The cause of aseptic loosening of prosthetic joint replacement components is unclear. Early experience with total joint arthroplasty was plagued by a number of problems that no longer exist as major impediments to long-term success. Improvements in the operating room environment and the use of prophylactic antibiotics have substantially reduced the high incidence of infection to less than 1%. Implant materials have long been considered biologically inert, but recent studies indicate that inflammatory reactions directed against the implanted materials may contribute to aseptic loosening. Currently, particulate debris from cement or polyethylene causing loosening of the prosthesis is the major problem in total joint arthroplasty. Significant data suggest a progression from a simple inflammatory reaction to complex immune responses against the biomaterials. The cellular responses to particles of polymethyl methacrylate, ultra-high-molecular-weight polyethylene, and alloys of cobalt-chromium and titanium have been assayed in vitro in patients with osteoarthritis, rheumatoid arthritis, and avascular necrosis who had total joint replacement. Elevated immunologic cell proliferation responses to both acrylic and cobalt chromium were observed in patients with aseptically loosened prostheses. These findings suggest that the development of a cellular response to particulate debris may be significant in the pathogenesis of aseptic loosening.

The immune response to implant materials in humans.

The etiology of aseptic loosening of prosthetic joint replacement components is unclear. Implant materials have been considered biologically inert, but recently studies indicate that inflammatory reactions directed against the implanted materials may contribute to aseptic loosening. Data suggesting a progression from a simple inflammatory reaction to complex immune responses against the biomaterials are reviewed. The cellular responses to particles of polymethylmethacrylate, ultrahigh molecular weight polyethylene, and alloys of cobalt-chromium and titanium were assayed in vitro to determine cell proliferation in patients with underlying diagnoses of osteoarthrosis, rheumatoid arthritis, and avascular necrosis who had joint replacement. Control populations were provided by patients with similar diagnoses who were preoperative surgical candidates. The underlying diagnoses did not seem to influence responses to particle stimulation. Elevated responses to both acrylic and cobalt-chromium were observed in patients with aseptically loosened prostheses. These findings suggest that the development of a cellular response to particulate debris may be significant in the pathogenesis of aseptic loosening.

Role of inflammatory mediators and adhesion molecules in the pathogenesis of aseptic loosening in total hip arthroplasties

Concentrations of prostaglandin E 2, interleukin-6, and interleukin-8 were determined in the hip joint synovial fluid of 20 patients undergoing primary (n = 12) and revision (n = 8) total hip arthroplasties. Levels of soluble adhesion molecules were also investigated in these patients. There was a significant and marked increase in levels of prostaglandin E 2 ( P < .001), interleukin-6 ( P < .011), interleukin-8 ( P < .0002), soluble intercellular adhesion molecule 1 ( P < .07), soluble vascular adhesion molecule 1 ( P < .0006), and soluble endothelial leukocyte adhesion molecule 1 ( P < .0003) in joint fluid of patients undergoing revision. On the basis of these observations, it is suggested that synovial fluid and its inflammatory contents could play a significant role in the pathogenesis of aseptic loosening in total hip arthroplasties.