An in vivo murine model of continuous intramedullary infusion of polyethylene particles (original) (raw)
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Continuous Infusion of UHMWPE Particles Induces Increased Bone Macrophages and Osteolysis
Clinical Orthopaedics and Related Research®, 2011
Background Aseptic loosening and periprosthetic osteolysis resulting from wear debris are major complications of total joint arthroplasty. Monocyte/macrophages are the key cells related to osteolysis at the bone-implant interface of joint arthroplasties. Whether the monocyte/macrophages found at the implant interface in the presence of polyethylene particles are locally or systemically derived is unknown. Questions/purposes We therefore asked (1) whether macrophages associated with polyethylene particle-induced chronic inflammation are recruited locally or systemically and (2) whether the recruited macrophages are associated with enhanced osteolysis locally. Methods Noninvasive in vivo imaging techniques (bioluminescence and microCT) were used to investigate initial macrophage migration systemically from a remote injection site to polyethylene wear particles continuously infused into the femoral canal. We used histologic and immunohistologic staining to confirm localization of migrated macrophages to the polyethylene particle-treated femoral canals and monitor cellular markers of bone remodeling. Results The values for bioluminescence were increased for animals receiving UHMWPE particles compared with the group in which the carrier saline was infused. At Day 8, the ratio of bioluminescence (operated femur divided by nonoperated contralateral femur of each animal) for the UHMWPE group was 13.95 ± 5.65, whereas the ratio for the saline group was 2.60 ± 1.14. Immunohistologic analysis demonstrated the presence of reporter macrophages in the UHMWPE particle-implanted femora only. MicroCT scans showed the bone mineral density for the group with both UHMWPE particles and macrophage was lower than the control groups. Conclusions Infusion of clinically relevant polyethylene particles, similar to the human scenario, stimulated systemic migration of remotely injected macrophages and local net bone resorption.
Biomaterials, 2000
Wear debris is considered to be one of the main factors responsible for aseptic loosening of orthopaedic endoprostheses. Whereas the response of cells in the monocytic lineage to foreign materials has been extensively studied, little is known about cells at the bone formation site. In the present study, we examined the hypothesis that the response of osteoblasts to wear debris depends on the chemical composition of the particles. We produced particles from commercially pure titanium (cpTi), Ti}6Al}4V (Ti-A), and cobalt-chrome (CoCr) and obtained ultrahigh molecular weight polyethylene (UHMWPE; GUR 4150) particles from a commercial source. The equivalent circle diameters of the particles were comparable: 1.0$0.96 m for UHMWPE; 0.84$0.12 m for cpTi; 1.35$0.09 m for Ti-A, and 1.21$0.16 m for CoCr. Con#uent primary human osteoblasts and MG63 osteoblast-like cells were incubated in the presence of particles for 24 h. Harvested cultures were examined by transmission electron microscopy to determine if the cells had phagocytosed the particles. Particles were found intracellularly, primarily in the cytosol, in both the primary osteoblasts and MG63 cells. The chemical composition of the particles inside the cells was con"rmed by energy-dispersive X-ray analysis. Morphologically, both cell types had extensive ru%ed cell membranes, less-developed endoplasmic reticulum, swollen mitochondria, and vacuolic inclusions compared with untreated cells. CpTi, Ti-A, and CoCr particles were also added to cultures of MG63 cells to assess their e!ect on proliferation (cell number) and di!erentiation (alkaline phosphatase activity), and PGE production. All three types of particles had e!ects on the cells. The e!ect on cell number was dependent on the chemical composition of the particles; Ti-A and CoCr caused a dose-dependent increase, while cpTi particles had a biphasic e!ect with a maximal increase in cell number observed at the 1 : 10 dilution. Alkaline phosphatase speci"c activity was also a!ected and cpTi was more inhibitory than Ti-A or CoCr. PGE production was increased by all particles, but the magnitude of the e!ect was particle-dependent: CoCr'cpTi'Ti-A. This study demonstrates clearly that human osteoblast-like cells and MG63 cells can phagocytose small UHMWPE, CoCr, Ti-A, and cpTi particles. Phagocytosis of the particles is correlated with changes in morphology, and analysis of MG63 response shows that cell proliferation, di!erentiation, and prostanoid production are a!ected. This may have negative e!ects on bone formation adjacent to an orthopaedic implant and may initiate or contribute to the cellular events that cause aseptic loosening by inhibiting bone formation. The e!ects on alkaline phosphatase and PGE release are dependent on the chemical composition of the particles, suggesting that both the type and concentration of wear debris at an implant site may be important in determining clinical outcome.
Particle disease: biologic mechanisms of periprosthetic osteolysis in total hip arthroplasty
Innate immunity, 2013
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...
Inflammatory Response to Implant Particulates in a Macrophage/Osteoblast Coculture Model
Calcified Tissue International, 1996
The purpose of this study was to further define the cellular response to titanium and polymethylmethacrylate (PMMA) particles in aseptic loosening, and to determine if the use of pamidronate may be effective in inhibiting bone resorption associated with this response. Macrophages and osteoblasts were cocultured to simulate the environment around an aseptically loose prosthesis. Macrophages were plated on the bottom of six well plates and osteoblasts were plated on culture dish inserts, and placed into the wells with the macrophages. Incubation of macrophages with PMMA in this system led to release of prostaglandin E (PGE 2), granulocyte macrophage-colony stimulating factor (GM-CSF), and interleukin-6 (IL-6). Incubation with titanium led to release of tumor necrosis factor (TNF) and IL-6. Exposure of calvaria to media from cells exposed to either PMMA or titanium led to release of calcium 45. Incubation of calvaria with pamidronate was able to inhibit release of calcium 45 associated with exposure to the macrophage/osteoblast/particle conditioned medium. Bone resorption at the interface between implant and bone is a consistent feature leading to loosening of orthopedic implants. By inhibiting bone resorption associated with the inflammatory response to implant particulates, pamidronate or other bisphosphonates may have clinical utility in the treatment or prevention or aseptic loosening. Aseptic loosening can be defined as the failure of the bond between implant and bone in the absence of infection. It is the major factor that limits the longevity of prosthetic reconstruction, and is the reason why these procedures are reserved for older individuals due to the relatively short lifespan of these implants. At the present time, there is no accepted medical or pharmacologic treatment for this problem. Aseptic loosening is characterized by resorption of bone leading to loss of fixation at the bone-implant interface. Retrieval studies have revealed cement and metal particulate wear debris within macrophages at the interface of loose prostheses [1-8]. Analysis of synovial fluid from loose implants, and medium from interface material cultured in vitro, has demonstrated the presence of mediators capable of stimulating bone resorption [9-12]. This has led to the theory that bone resorption in aseptic loosening results from an inflammatory response to wear debris at the bone-implant interface. Prior studies on the macrophage response to orthopedic implant materials have concentrated primarily on the effects of these particles on macrophages in isolation [13-16]. At the interface of the loose prosthesis, however, macrophages phagocytizing particles are seen in close proximity to osteoblasts which are known to respond to mediators released from macrophages, and also to be important in bone resorption. In recent studies from this laboratory, the potential importance of macrophage/osteoblast interactions in the response to implant particulates has been studied. It was demonstrated that following polymethylmethacrylate (PMMA) particle phagocytosis by macrophages, the presence of osteoblasts was necessary to stimulate osteoclast migration onto a calcified substrate (dentin) [17]. Further studies on the macrophage/osteoblast interaction have demonstrated that exposure of macrophages to PMMA particles leads to the release of tumor necrosis factor alpha (TNFa) which then stimulates osteoblasts to produce granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin 6 (IL 6), and prostaglandin E2 (PGE 2), all of which are known to be of potential importance in bone resorption [18, 19]. These prior studies demonstrate the importance of the osteoblast response to mediators released by macrophages in aseptic loosening. Unfortunately, these experiments do not take into account the potential effects of mediators released by osteoblasts upon macrophages. In addition, the studies focused exclusively on the response to PMMA particles, whereas at the interface of the loose prosthesis, metal particles such as titanium are also present. To more accurately depict the cellular environment of the loose prosthesis in this study, macrophages were exposed to either PMMA or titanium particles with osteoblasts in co-culture.
Effects of orthopaedic wear particles on osteoprogenitor cells
Biomaterials, 2006
Wear particles from total joint arthroplasties are constantly being generated throughout the lifetime of an implant. Since mesenchymal stem cells and osteoprogenitors from the bone marrow are the precursors of osteoblasts, the reaction of these cells to orthopaedic wear particles is critical to both initial osseointegration of implants and ongoing regeneration of the periprosthetic bed. Particles less than 5 mm can undergo phagocytosis by mature osteoblasts, with potential adverse effects on cellular viability, proliferation and function. The specific effects are dependent on particle composition and dose. Metal and polymer particles in non-toxic doses stimulate proinflammatory factor release more than ceramic particles of a similar size. The released factors inhibit markers of bone formation and are capable of stimulating osteoclast-mediated bone resorption. Mesenchymal stem cells and osteoprogenitors are also profoundly affected by wear particles. Titanium and polymethylmethacrylate particles inhibit bone cell viability and proliferation, and downregulate markers of bone formation in a dose-and time-dependent manner. Future studies should delineate the molecular mechanisms by which particles adversely affect mesenchymal stems cells and the bone cell lineage and provide strategies to modulate these effects.
Journal of International Medical Research, 2006
Osteolysis induced by ultra-high molecular weight polyethylene wear particles is the major cause of long-term failure of artificial joints. We examined the effects of wear particles on bioactivity by analysing the biophysical aspects of particle phagocytosis. We estimated the maximum number of internalized particles (the phagocytic capacity) for particles of various sizes and shapes. We demonstrated that elongated particles had a smaller phagocytic capacity than spherical particles of the same volume. A review of the literature showed that the ratio of particle concentration (number of particles/number of cells) to phagocytic capacity is critical for particle-induced biological responses. When this ratio was < 1, the biological response was approximately proportional to the ratio itself. When this ratio was > 1, limited changes in the biological response were observed. The saturation level of the phagocytic capacity for a particle population appears to reflect the degree of po...
Polyethylene and titanium particles induce osteolysis by similar, lymphocyte-independent, mechanisms
Journal of Orthopaedic Research, 2005
Periprosthetic osteolysis is a major clinical problem that limits the long-term survival of total joint arthroplasties. Osteolysis is induced by implant-derived wear particles, primarily from the polyethylene bearing surfaces. This study examined two hypotheses. First, that similar mechanisms are responsible for osteolysis induced by polyethylene and titanium particles. Second, that lymphocytes do not play a major role in particle-induced osteolysis. To test these hypotheses, we used the murine calvarial model that we have previously used to examine titanium-induced osteolysis. Polyethylene particles rapidly induced osteolysis in the murine calvaria 5-7days after implantation. The polyethylene-induced osteolysis was associated with large numbers of osteoclasts as well as the formation of a thick periosteal fibrous tissue layer with numerous macrophages containing phagocytosed polyethylene particles. Polyethylene-induced osteolysis was rapidly repaired and was undetectable by day 21 after implantation. Lymphocytes were noted in the fibrous layer of wild-type mice. However, the amount of osteolysis and cytokine production induced by polyethylene particles was not substantially affected by the lack of lymphocytes in PfplRag2 double knock out mice. All of these findings are similar to our observations of osteolysis induced by titanium particles. These results provide strong support for both of our hypotheses: that similar mechanisms are responsible for osteolysis induced by polyethylene and titanium particles and that lymphocytes do not play a major role in particle-induced osteolysis.
Osteolysis induced by ultra-high molecular weight polyethylene wear particles is the major cause of long-term failure of artificial joints. We examined the effects of wear particles on bioactivity by analysing the biophysical aspects of particle phagocytosis. We estimated the maximum number of internalized particles (the phagocytic capacity) for particles of various sizes and shapes. We demonstrated that elongated particles had a smaller phagocytic capacity than spherical particles of the same volume.
Particle bioreactivity and wear-mediated osteolysis
The Journal of Arthroplasty, 2004
This review focuses on wear debris-mediated osteolysis, a major factor compromising the long-term success of total joint arthroplasty. Studies on retrieved implants and animal models, as well as in vitro studies on particle bioreactivity, suggest that wear-mediated periprosthetic osteolysis is unlikely to be caused solely by 1 particular cell type or particulate species, but is rather the cumulative consequence of a number of biological reactions. Our recent findings suggest 3 novel mechanisms of particle bioreactivity that may contribute to osteolysis: 1) exacerbated inflammation caused by elevated reactive oxygen species production by activated macrophages and osteoclasts, (2) impaired periprosthetic bone formation secondary to disrupted osteogenesis, and (3) compromised bone regeneration resulting from increased cytotoxic response of mesenchymal osteoprogenitor cells. Understanding the pathogenesis of wear-mediated osteolysis is needed to improve orthopedic implant biocompatibility and wear reduction, and to develop effective pharmacotherapies.
Acta Biomaterialia, 2016
Periprosthetic osteolysis (PO) leading to aseptic loosening, is the most common cause of failure of total hip replacement (THR) in the mid-to long-term. Polyethylene (PE) particulates from the wear of prosthesis liners are bioactive and are implicated in the initiation and or progression of osteolysis. Evidence exists that cells of the osteoblast/osteocyte lineage are affected by PE particles and contribute to the catabolic response by promoting osteoclastic bone resorption. In this study, we hypothesised that osteocytes contribute directly to PO by removing bone from their perilacunar matrix. Osteocyte responses to ultrahigh molecular weight PE (UHMWPE) particles were examined in vitro in human primary osteocyte-like cultures, in vivo in the mouse calvarial osteolysis model, and in the acetabulum of patients undergoing revision total hip replacement (THR) surgery for PO. Osteocytes exposed to UHMWPE particles showed upregulated expression of catabolic markers, MMP-13, carbonic anhydrase 2 (CA2), cathepsin K (CTSK) and tartrate resistant acid phosphatase (TRAP), with no effect on cell viability, as assessed by Caspase 3 activity. Consistent with this catabolic activity causing perilacunar bone loss, histological analysis of calvarial sections from mice exposed to UHMWPE revealed a significant (p < 0.001) increase in osteocyte lacunar area (Lac.Ar) compared to sham-operated animals. Furthermore, acetabular biopsies from patients with PO also showed significantly (p < 0.001) increased osteocyte lacunar size in trabecular bone adjacent to PE particles, compared with osteocyte lacunar size in bone from primary THR patients. Together, these findings suggest a previously unrecognised action of UHMWPE wear particles on osteocytes, which directly results in a loss of osteocyte perilacunar bone. This action may exacerbate the indirect pro-osteoclastic action of UHMWPE-affected osteocytes, previously shown to contribute to aseptic loosening of orthopaedic implants.