Pathophysiologic Reactions to UHMWPE Wear Particles

28  Pathophysiologic Reactions to UHMWPE Wear Particles Marla J. Steinbeck, MT(ASCP), PhD* and Sai Y. Veruva, PhD Candidate** School of Biomedical Engineering and Health Sciences; Department of Orthopaedic Surgery, Drexel University College of Medicine, Philadelphia, PA, USA ** School of Biomedical Engineering and Health Sciences, Drexel University, Philadelphia, PA, USA *

28.1 Introduction From a clinical perspective, implants for total joint replacement must contribute to a biologically favorable and mechanically stable environment to provide a satisfactory long-term outcome. One of the most important factors determining the success of a total joint replacement is implant wear over time and the associated adverse biologic reactions elicited by wear debris [1], (Chapter 33). The most obvious gross, clinical manifestation associated with implant wear debris generation is bone loss (osteolysis typically after 5–10 years; Figure 28.1), which has been identified as a major reason for implant loosening and the need for revision surgery after total hip replacement. In 1977, a seminal paper by Hans-Georg Willert demonstrated macrophage activation by ultra-high molecular weight polyethylenes (UHMWPE) wear debris that is generated by intended motion of the articulating implant surfaces, and by the movement of the implant against surrounding bone [2]. These initial observations led to numerous studies characterizing the chronic inflammatory response to foreign debris accumulation in periprosthetic tissue. The challenge in assessing the pathophysiologic response to wear debris associated with a joint implant is to accurately characterize UHMWPE wear debris (amount, size, and shape) and the surrounding tissue response at both early and late implantation times. Another confounding factor is determining the distribution of wear debris, which is found locally and at more remote sites along the implant interface, as well as other organs. Distribution of the wear debris occurs as a result of cyclic loading of an articulating joint implant resulting in intermittent waves of increased joint fluid pressure [3]. The local dissemination of particles is limited by the density of the surrounding tissue where large particles are trapped in dense, collagen-rich joint UHMWPE Biomaterials Handbook Copyright © 2016 Elsevier Inc. All rights reserved.

pseudosynovial tissue, while smaller particles are able to move more freely. A cadaveric study showed that UHMWPE wear debris was disseminated to the spleen, liver, and lymph nodes after both primary and revision surgeries [4]. Most of the disseminated particles were smaller than 1 mm, but particles as large as 50 mm have been identified in abdominal lymph nodes. Lymphatic transport through perivascular lymph channels, as free or phagocytosed particles within macrophages or dendritic cells, is the most probable route for wear debris distribution. Furthermore, a reactive granular histiocytosis to wear debris has been observed in regional lymph node reactions, which results in the loss of lymph node architecture and focal necrosis [5,6]. Nonetheless, the nature and ultimate fate of wear debris, and the implications of longterm systemic exposure, still remain among the least understood aspects of joint arthroplasty. The overall pathophysiologic response to UHMWPE wear debris is a complex process, involving a number of cell types and progressive local and systemic changes with increasing implantation times. Patient-specific factors or responses to wear debris further confound a complete understanding of this process by introducing additional variability of the host response to UHMWPE debris. Potential factors involved in individual biological responses to wear debris include single nucleotide polymorphisms in genes encoding for a number of macrophage inflammatory factors, although only interleukin (IL)-6 and tumor necrosis factoralpha (TNF-a) have been reported by multiple groups [7–12]. Moreover, the undetectable progression of inflammation, biochemical, and morphological changes that occur in tissues surrounding the implant impose a major challenge, as tissues taken at the time of revision surgery only reflect the accumulated changes that led to clinical failure. For this reason, cadaveric studies on well-fixed implants are also important. 506

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diagnostic and treatment strategies to mitigate specific host responses. The development of diagnostic markers that reflect tissue–device interactions will also avoid relying heavily on patient–reported outcomes that are based on the subjective perception of pain and functional expectations. Hence, a comprehensive and detailed understanding of the biological reactions to the implant as a result of wear debris is imperative for advancing the field of a­ rthroplasty.

28.3  Immune System

Figure 28.1 Radiograph with pronounced regions of acetabular and femoral osteolysis (radiolucency ­indicated with red arrows) from a gamma-air sterilized UHMWPE hip replacement revised 11.4  years postimplantation.

28.2  Rationale for Evaluating Tissue Responses There is an overall need to understand the pathophysiologic responses to wear debris in the hope of developing both early diagnostic tests (serum or urine biomarkers) and treatment modalities to suppress or alleviate these responses [13–15]. Insights into the loss of total joint replacement function have been gained by analyzing cellular and molecular changes in periprosthetic tissues. Numerous studies have shown an inflammatory response to wear debris, however, more detailed analysis of these tissues is necessary to understand specifics of the immune response as well as tissue damage/necrotic responses that contribute to the implant-related biological responses. Understanding the biological responses will provide a basis for assessing the success and failure of various implant biomaterials and designs, and will assist in improving implant biotechnology, ultimately resulting in better implant longevity. For those patients with existing implants, this information will accelerate the development of personalized medicine by identifying

Since the seminal work by Hans-Georg Willert demonstrating macrophage activation by UHMWPE wear debris, interest in understanding the complete immune response in periprosthetic tissue has exploded [2]. For most nonimmunologists, this complex area is difficult to grasp, but hopefully, the following information will provide the basis for a better understanding of the immune system. The cells that carry out the immune response are called white blood cells (WBC) or leukocytes [16]. Leukocytes are subdivided into two groups of cells. The first group is the myeloid cells, which are cells that contain cytosolic granules and include neutrophils, eosinophils, basophils, and monocytes. These cells undergo maturation in the bone marrow and then enter the bloodstream. If needed for defense of the host, they are recruited to various tissues in response to infectious agents or tissue injury. During recruitment, the leukocytes become tethered, roll, and eventually adhere to activated vascular endothelial cells lining the postcapillary venules of the affected tissue. The cells then migrate through the endothelial cell layer and enter (infiltrate) the tissue. Monocytes, unlike the other myeloid cells, are found in most tissues as resident cells. After recruitment to the tissues, they are called macrophages, and depending on the specific tissue they may be referred to as histiocytes (connective tissue), microglial cells (brain), Kupfer cells (liver), etc. Macrophages make up part of the body’s first line of defense against infectious agents or other foreign material, including bacterial products, chemicals, drugs, pollen, food, animal hair, and dander, or more specifically to the topic at hand, wear debris generated by joint implant use. When activated, macrophages can assume either the “classically activated,” proinflammatory M1 phenotype or the “alternatively activated,” anti-­ inflammatory and tissue reparatory M2 phenotype. The second group of leukocytes is comprised of lymphocytes or lymphoid cells. Lymphocytes

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are subdivided into B cells that undergo complete maturation in the bone marrow and T cells that mature in the thymus. B cells develop into plasma cells that produce and release antibodies, while T cells form helper (Th) or cytotoxic (Tc) T cells. Helper T cells can be further subdivided based on cytokine ­profiles into type 1 (Th1), type 2 (Th2) or regulatory T cells (Treg). The Th1 are involved in cell-mediated immunity and produce factors that stimulate phagocytosis and Tc activation. Th2 cells are involved in the humoral immune response and promote B cell activation and antibody production. Lastly, Treg cells specialize in mediating immunesuppression and maintain tolerance to self-antigens. Disruption in the function of Treg cells is the primary cause of chronic inflammatory and autoimmune diseases.

28.3.1  Innate and Adaptive Immune Response The immune response is divided into innate (nonspecific) immunity and adaptive (antigen-specific) immunity. The innate immune system is constitutively on guard, reacts immediately, and is responsible for the initial defense against infectious agents and removal of damaged cells and any foreign material. This response is not specific, and therefore, it is not dependent on the type of foreign body or nonself component. The innate immune system includes the physical (skin and mucosal membranes) and chemical (mucous and antimicrobial peptides) barriers, blood proteins (acute phase proteins and complement), cytokines, chemokines, phagocytic cells (neutrophils, macrophages, and dendritic cells), and natural killer cells (NK). Phagocytic cells undergo differentiation in the bone marrow, enter the peripheral blood, and macrophages are found as resident cells within tissues (as mentioned earlier). These cells perform various host defense functions that rely on phagocytic uptake of infectious agents, damaged host cells, and foreign material. However, unlike neutrophils and macrophages, dendritic cells are not thought to play a major role in the host defense against infectious agents. NK cells undergo maturation in the bone marrow and although most contain granules, but they are classified as large, cytotoxic lymphocytes rather than granulocytes. After entering the bloodstream, they accumulate in secondary lymphoid tissues, such as the tonsils, lymph nodes, and spleen. The natural killing by these cells does

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not require prior host exposure to the target cells and is mediated by granule exocytosis. The major function of the NK cell is to remove virally infected and abnormal host cells. Adaptive, or specific immunity is controlled by lymphocytes and occurs after exposure to any foreign antigenic substance that is specifically recognized by these cells. Unlike the innate immune response, the adaptive immune response is antigenspecific, reacting only with the substance that induces activation, thereby increasing response time as the activated cells undergo clonal expansion. This arm of the immune system also exhibits immunological memory. It “remembers” that it has encountered a foreign antigen and will react more rapidly on subsequent exposure to the same molecule. Memory cells play a major role in both T cell-mediated and B cell, humoral and adaptive immunity. Every adaptive immune response involves the recruitment and activation of not only the effector T and B cells, but also Treg immune suppressor cells. The balance between these cell populations is critical for the appropriate control of the quality and magnitude of the adaptive immune response, and for establishing tolerance to self-antigens. The adaptive immune response is dependent on both macrophages and dendritric cells, which act as antigen-presenting cells. These cells degrade phagocytosed or ingested biological material and present degraded proteins (antigens) on the cell surface to Th1 and Tc lymphocytes along with appropriate costimulatory molecules (e.g., major histocompatibility complex class II). The dendritic cell is recognized as the most potent antigen-presenting cell, as these cells present antigens, secrete cytokines and direct Th cell differentiation, maturation of B cells, and B cell memory responses. The presentation of processed surface antigens by dendritic cells to lymphocytes leads to lymphocyte activation. NK cells can also play a role in the adaptive immune response by secreting cytokines that enhance T and B cell responses, and subsequent immunological memory.

28.3.2  Cytokines and Chemokines Cytokines are cellular proteins (chemical messenger proteins) that mediate inflammation and communication between cells of the immune system, but can have effects on other local cell types. These proteins are released by cells and affect the behavior of other cells that bear receptors for them. The general categories of cytokines include ILs, which at the present

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time include IL-1 to IL-37, TNF a − b and interferons a − g [17]. Chemokines (or chemotactic cytokines) are members of a large family of extracellular immunoregulatory proteins that primarily act as chemoattractants for immune cells, recruiting them to areas containing infectious agents, damaged host cells or other foreign substances. Differentially expressed by most cell types, chemokines can be loosely divided into two main immunologic groups: homeostatic chemokines, which are expressed constitutively; and inflammatory chemokines, which are induced by infection and injury or in the setting of inappropriate inflammation. Like cytokines, these proteins are produced by immune cells, as well as other cell types (e.g., tissue fibroblasts) in response to specific stimuli.

28.4  Immunologic Responses to Joint Replacement UHMWPE Wear Debris Following a total hip or knee arthroplasty, a newly formed joint capsule or pseudosynovial membrane is formed around the implant within the joint space [18–21]. First, capsular tissue becomes established, followed by the formation of an intermediate and

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highly vascularized fibrous membrane [2]. At the time of revision surgery for aseptic implant loosening, an extended and thickened fibrous membrane with increased numbers of histiocytes, focal areas of necrosis, and decreased vascularization is typically present [22]. The predominant cells found in the intermediate fibrous membrane and other periprosthetic tissues include fibroblasts, recruited peripheral blood monocytes, histiocytes (resident macrophages), recruited and resident dendritic cells, and multinucleated giant cells [6,23–30]. Interspersed throughout the tissue are both micron (typically from gamma airsterilized UHMWPE components) and submicron UHMWPE debris [31–39]. Small and large UHMWPE particles (Figure 28.2), ranging in size from 0.3/0.5 mm to 10 mm, are ingested by phagocytosis and are found within phagosomes, which fuse with lysosomes within the cell to form phagolysosomes [40–42]. For larger particles, typically >10  mm, histiocytes/macrophages fuse to form multinucleated giant cells in a failed attempt to ingest these particles (Figure 28.3). The actual or attempted ingestion of particles, referred to as phagocytosis and frustrated phagocytosis, respectively, occurs through nonspecific receptors on the cell surface and results in cell activation and the release of proinflammatory cytokines such as TNF-a, IL-1b, and IL-6 (Figure 28.4). Smaller particles (<0.3/0.5  mm) are taken up by a

Figure 28.2  Small and large UHMWPE wear debris observed in situ in periprosthetic hip tissue using transmitted and polarized light microscopy. (A) Phagocytic histiocytes shown in hematoxylin and eosin stained sections contained (B) micron and submicron-sized birefringent UHMWPE wear debris; (C) hematoxylin and eosin stained sections from gamma-air sterilized UHMWPE hip replacement revised 15.6  years postimplantation contained (D) large birefringent UHMWPE wear debris (red arrows). 200× magnification.

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Figure 28.3  Inflammatory changes in periprosthetic hip tissue in response to gamma air-sterilized UHMWPE wear debris. (A) CD68 antibody stain showing histiocytes (red arrows), 11 years postimplantation. Main image: 200× magnification; (B) foreign body giant cell (red arrow) with internalized UHMWPE wear debris, 15.4 years postimplantation. Left inset shows giant cell and right inset shows UHMWPE wear debris that is exhibiting birefringence under polarized light. Main image: 100× magnification. All inset images are enlarged by 200% relative to original image.

process called pinocytosis, which occurs to a greater extent in activated macrophages [41,43]. Pinocytosis does not directly lead to cellular activation although endosome (fused pinocytotic vessels and lysosomes) rupture, the release of cathepsin and the activation of NALP3 inflammasome can contribute to proinflammatory cytokine formation and release [44]. Phagocytic activation of macrophages marks the beginning of a chronic foreign body inflammatory reaction initiated by the accumulation of UHMWPE wear debris and the inability of the phagocytic cells to degrade the ingested or uningested wear debris. During the process of attempted degradation within the formed phagolysosome, the UHMWPE

particles are exposed to protein-degrading enzymes (e.g., matrix metalloproteinases) [45–48] and reactive oxygen and nitrogen species (ROS and RNS) [49–51]. ROS production occurs when NADPHoxidase 2 (NOX2) within the plasma membrane is activated in response to particle phagocytosis or frustrated phagocytosis (Figure 28.5) [52]. The ROS superoxide anion is produced by NOX2, and this is converted either spontaneously or enzymatically to hydrogen peroxide, and the highly reactive species, singlet oxygen, hydroxyl radical, and hydroxyl anion [53–55]. RNS are produced by inducible nitric oxide synthase (iNOS), which is upregulated in response to ROS (e.g., oxidative stress) and proinflammatory

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Figure 28.4  Diagram of inflammatory changes that can lead to osteolysis. (A) The infiltration of monocytes and the activation of resident synovial fibroblasts and histiocytes in response to UHMWPE wear debris leads to the production of chemokines, cytokines, and osteoclastogenic factors: TNF-a, IL-1b, IL-6, RANKL, IL-8, MCP-1, and M-CSF. Giant cells form in response to larger wear debris. Monocyte–macrophages differentiate into osteoclasts, which are the cells responsible for bone resorption. The production of reactive oxygen species (ROS) by NADPHoxidase 2 (NOX2) within activated macrophages can lead to oxidative stress. This in turn triggers the upregulation of osteoinflammatory–oxidative stress responsive factors, which include iNOS, high mobility group protein-B1 (HMGB1), cyclo-oxygenase 2 (COX2), and the formation of ROS and reactive nitrogen species (produced by iNOS) end products 4-hydroxynonenal (4-HNE) and nitrotyrosine (NT). (B) UHMWPE particles ranging in size from 0.5  mm to10  mm are ingested by phagocytosis and are found within phagosomes, which fuse with lysosomes, which contain digestive enzymes (e.g., metalloproteases, cathepsins), within the macrophage–histiocyte to form phagolysosomes. Smaller particles are taken up by a process called pinocytosis. Pinocytosis does not directly lead to cellular activation although endosome rupture can contribute to proinflammatory cytokine formation following NALP3 inflammasome activation. The attempted ingestion of large particles is referred to as frustrated phagocytosis. ROS production occurs when NOX2 within the plasma membrane is activated in response to particle phagocytosis or frustrated phagocytosis. Depending on the differentiation stage of the cell, cytokines and HMGB1 may be upregulated by ROS activation of the transcription factor nuclear factor kappa B (NFkB) and/or released from secretory vesicles. The upregulation of iNOS and COX2, in response to ROS, results in the generation of reactive nitrogen species (RNS), which leads to NT formation, and the production of the proinflammatory factor PGE2, respectively.

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Figure 28.5  CD3 immunostained T cells (red arrows) and foreign body giant cell (green arrow) localized with UHMWPE wear debris (yellow arrows) from a gamma-air sterilized UHMWPE hip replacement revised 14.2 years postimplantation. 200× ­magnification.

cytokine production [56,57]. This enzyme produces nitric oxide, which combines with superoxide anion to form the more reactive peroxynitrite; subsequent reactions produce addition RNS [55,58–60]. While affective in killing infectious agents (e.g., bacteria) [54,61–63], digestive enzymes, ROS and RNS cannot degrade the UHMWPE particles. Ultimately, the phagolysosomes and endosomes rupture, the cell dies, and the particles are released back into the tissue along with the digestive enzymes and ROS and RNS, which cause tissue damage/necrosis. Thus, without the ability to remove the wear debris stimulus, the inflammatory response continues, and rather than achieving a resolution thereby returning the tissue to a normal functional state (homeostasis), further tissue damage occurs. Cells and factors involved in controlling the amount of inflammation and tissue damage are discussed at the end of this section. The innate immune response induced by wear particles is a chronic inflammatory and nonspecific foreign body reaction. This reaction may also involve mast cells within the periprosthetic tissue [64,65]. Mast cells are immune cells found in mucosal and connective tissue, in relatively low numbers. When activated, the number of mast cells can increase dramatically, and the release of enzymes and other mediators by these cells can stimulate fibroblast proliferation, vascularization, and inflammation. These cells are involved in the defense against pathogens, play a role in allergic, and anaphylaxis reactions, but also tissue healing. Based on numerous studies of periprosthetic tissues, it is the activation of both recruited and resident cells, by either phagocytosis of wear debris or through contact between particles and cell membrane surface

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receptors such as toll-like receptors (TLRs 2 & 4), and scavenger receptors, that leads to the production and release of cytokines, chemokines, and growth factors by these cells [25,44,66–72]. During the acute phase, the chemokine, MCP-1, in particular, is an immediate and early stress response factor that is released in response to wear debris and is primarily involved in the systemic recruitment of monocytes to the joint space. Once released into the bloodstream, the chemokine binds to the receptors, CCR2A and CCR2B, expressed on monocytes and activated NK cells [73,74]. In most of the inflammatory reactions, the acute phase is typically a short-lived response during which proinflammatory cytokines and chemokines including IL-1a, IL1b, IL-6, TNF-a, IL-8, and MCP-1 are produced and released by activated fibroblasts, macrophages, and mast cells [20,75–77]. Other mediators of inflammation found at high levels in periprosthetic tissue include prostaglandin E2 (PGE2, produced by cyclooxygenase 2, COX2) and iNOS [19,21,51,77–79]. The presence of all of these factors and undigested wear debris causes the acute inflammation to progress into a chronic inflammatory response. However, given the continuous introduction of wear particles into the tissue, the acute inflammatory phase may be recurrent. While the focus has been on the innate immune response, low numbers of T cells have been observed in periprosthetic membrane tissue [30,80,81]. The role of T cells is not clear. In a subset of patients, however, there may be an immune response that is directed at UHMWPE particles coated with immunostimulatory proteins [82]. These proteins may be host proteins released as a result cell death [83] or host proteins modified by proteases, ROS and/or RNS damage [84]. This reaction is a Type II antibody-mediated hypersensitivity reaction, which is mediated by Th2 cells, B cells (plasma cells), and effector cells (typically monocytes/macrophages). The tissue damage associated with this response is mediated by activated macrophages and the release of lysosomal granule contents and the production of ROS and RNS. Type IV hypersensitivity or delayed-type hypersensitivity reactions may occur in response to the binding of small proteins (haptens, <1000 Da) or other host cell material to UHMWPE particles. However, this type of reaction has predominantly been observed when metal debris or ions are present in the periprosthetic tissue (Figure 28.6). Type IV hypersensitivity reactions are mediated by Th1 cells and the tissue damage associated with this immune reaction is mediated by Tc cells. Another subset of T cells producing IL-17 was recognized in the early 2000s [85–87]. Th17 cells have a distinctive cytokine profile which includes I­L-17,

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Figure 28.6  Periprosthetic hip tissue revised 19 years postimplantation contained both metal (red arrow) and UHWMPE wear debris. (A) Hematoxylin and eosin stained sections under transmitted light showed metal and (B) polarized light revealed UHMWPE wear in the same region. 100× magnification.

TNF-a, and RANKL (receptor activator of nuclearreceptor factor NFkB ligand). These factors affect neutrophil, monocyte/macrophage, and osteoclast mobilization, differentiation, and activation [86]. Osteoclast formation, bone resorption, and osteolysis are discussed in Section 28.6. Th17 cells play a role in fighting bacterial infections, but are also involved in autoimmune diseases directed against altered host (self) proteins. These cells are found in the synovial membrane of patients with autoimmune rheumatoid arthritis, and the expression of extracellular matrix proteins and integrin receptors by synovial lining cells are similar in both rheumatoid arthritis and in tissues from patients with aseptic loosening of total hip replacements [26,88]. The involvement of NK cells in the removal of damaged cells or cells that have lost “self recognizing” surface receptors in periprosthetic tissues has not been extensively investigated, although these cells have been found in revision tissues [89]. Additionally, these cells produce both proinflammatory cytokines that enhance M1 responses and antiinflammatory cytokines that promote M2 responses [90–92]. The involvement of T cell subsets and NK cells in periprosthetic tissue inflammation associated with UHMWPE wear debris will require additional studies. Although the focus has been predominantly on the wear debris stimulated proinflammatory responses, following this is an anti-inflammatory response that attempts to control inflammation and maintain tissue homeostasis. Cells involved in the anti-inflammatory response include regulatory macrophages (M2), Th2 cells that promote M2 cell differentiation by secreting anti-inflammatory cytokines IL-4 and IL-10, dendritic cells and possibly Treg and NK cells. Similarly, the inflammatory mediated damage to the surrounding tissue promotes chronic inflammation (e.g., the release of cell damage proteins referred to as alarmins that bind to TLRs). However, it also initiates a tissue

healing response involving fibroblasts and possibly stem cells and/or mast cells. Recently, Gallo et al. proposed that to gain a full understanding of periprosthetic osteolysis, and possibly the difference in individual responses, these homeostatic mechanisms need to be understood in relationship to the proinflammatory, osteolytic, and osteoblastic bone formation processes [93]. It is important to note that the balance between bone formation and bone resorption (bone remodeling) is tightly controlled and in the presence of wear debris, this balance is altered and favors bone loss. There is also evidence that osteoblast differentiation from progenitor cells and bone formation are affected by the ingestion of smaller wear debris by these cells [94,95].

28.5  In Vitro and In Vivo Models Used to Study the Immune Response to UHMWPE Wear Debris To study the direct effects of UHMWPE wear debris on monocyte/macrophage activation and to gain insight into the host response, UHMWPE particles with characteristics similar to those found in periprosthetic tissues have been added to cells in culture. Exposure to UHMWPE wear debris within the most clinically relevant size range (<10 mm) results in isolated blood monocyte or peritoneal macrophage activation, measured as an increase in the production of IL-1, IL-6, and TNF-a in culture [96–99]. Submicron particles (<1.0 mm) were found to be more biologically active, as the highest amount of proinflammatory cytokine production was observed in response to these particles compared to particles that were larger than 1 mm. In addition to size-based responses, elevated numbers of particles have been found at all locations in the periprosthetic tissue where chronic

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foreign-body reactions occur. This suggests that the number of particles may regulate monocyte/macrophage recruitment and subsequent activation. In vitro studies have shown that the amount of proinflammatory cytokines released was dependent on the ratio of particles to cells [42,96]. In studies by Green et al., the volume of particles was related to the cell number at two different concentrations, 10 mm3:1 or 100 mm3:1. Particles in the 0.24 ± 0.094 mm size range, using isolated monocytes which ingest smaller particles than tissue macrophages, caused the greatest amount of IL-1, IL-6, and PGE2 to be released when the ratio of particles to cells was 10 mm3:1. At the higher ratio, the larger-sized particles caused an increased release of proinflammatory cytokines. Particle composition also affected the release of proinflammatory cytokines by cultured monocytes [100–102]. Specific wear morphologies can also instigate and affect the biological response in periprosthetic tissue, as the smallest phagocytosable size for round particles was 0.5 mm [97]. To further investigate the effect of particle shape, Fang et al. (2006) developed an inverted monocyte/macrophage cell culture system and generated wear particles of varying size and shapes [103]. Their findings showed that spherical particles of the same volume were ingested to a greater extent by monocytes/macrophages in culture than the elongated particles. Thus, in vitro studies have shown that the biological response of monocytes/macrophages to UHMWPE wear debris is mediated by a variety of specific particle characteristics, including size, number, and shape. As the pathophysiologic response to wear debris is not limited to the effects on monocytes/macrophages alone, animal models have been developed to study the in vivo response to wear debris. These animal models include rat [104,105], canine [106], rabbit, [107] and mouse models [108–111]. In general, particles within a 0.1–10 mm size range either generated or isolated from periprosthetic tissues induced a local inflammatory response, which was increased as the particle numbers increased. Interestingly, Yang et al. [112] injected globular and elongated UHMWPE debris into air pouches on the backs of mice and showed that particles with large aspect ratios induced higher levels of TNF-a and IL-1b production, relative to globular particles with similar surface area. In a prospective study, Ren at al. showed that elongated particles also initiated more significant upregulation of both RANK and RANKL gene expression in mouse pouch tissues that led to enhanced osteoclastogenesis [113,114]. These results are interesting because in one in vitro cell study, globular

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particles were preferentially ingested by monocytes/ macrophages in culture [103]. While most animal studies have been based on a single bolus or injection of UHMWPE particles, more recent rat and mouse models have incorporated microdiffusion pump systems to provide continuous infusion of UHMWPE particles [115,116]. The continuous infusion of wear debris is more similar to wear generation within the joint, making this a more clinically relevant model. Regardless, both the deposition of UHWMPE particles using a single bolus approach and continuous infusion into the mouse femoral shaft lead to the infiltration of blood monocytes to sites of wear debris accumulation and a local macrophage–histiocyte response [116,117]. Animal models have also been used to evaluate potential treatments for inflammation and subsequent osteolysis in response to UHMWPE and titanium particles. The anti-inflammatory treatments included TNF-a antagonists [110,118], a COX2 inhibitor (COX2 produces PGE2) [119], as well as other genetic modifications or local delivery of antiinflammatory cytokines to modulate the inflammatory response [120–125]. Treatments targeting osteoclasts and bone resorption included the RANKL receptor inhibitor, osteoprotegrin (OPG), [126] and bisphosphonates [127], RANK knockout mice [128] and adenovirus OPG gene transfer [129]. However in humans, there are concerns about the use of bisphosphonates and other systemic treatments in regards to adverse systemic responses. For example, antiTNFa treatments may attenuate normal immune reactions leaving the individual susceptible to infectious agents such as bacteria. Furthermore, the inhibition of single proinflammatory cytokines has been ineffective in human clinical trials. It has been suggested that the failure of such treatments may be attributed to the compensatory role of NFkB activation by other wear-induced cytokines [130,131]. Thus, targeting downstream activity of NFkB is a potentially promising strategy to mitigate osteolysis. Other strategies for treatment include interfering with the chemotaxis of monocytes and targeting the polarization of resident and recruited macrophages into predominantly anti-inflammatory M2 macrophages. To interfere with chemotaxis, an MCP-1 receptor antagonist was used in mice and it dramatically reduced the migration of macrophages to the site of continuous infusion of UHMWPE particles [132]. To modulate macrophage polarization toward the M2 phenotype, IL-4 or IL-13 was injected into mice resulting in not only the reduction of particle-induced TNF-a and RANKL production, but also the number of ­osteoclasts [92,133].

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While these therapeutic treatments have shown promising outcomes in rodent models, they have not been tested in the patient population and potential side effects have not been evaluated. The major drawback of animal studies is that based on the short duration of the experiments, the immune response to UHMWPE wear does not necessarily correlate with the response observed in human tissue after years of implantation [134]. Furthermore, while it is fairly straightforward to deliver a treatment locally in rodents to prevent adverse systemic responses, finding a local delivery approach for the human population is more challenging.

28.6  Inflammatory and Noninflammatory Histopathologic Changes in Periprosthetic Tissues that Promote Heterotopic Ossification and/or Osteolysis In addition to the inflammatory response observed in periprosthetic tissues, other morphologic changes can take place in tissue and bone surrounding the implant. These changes include tissue fibrosis, necrosis, fibrocartilage formation, heterotopic ossification, (Figure 28.7) and last, but certainly not the least, osteolysis of the surrounding bone. Gallo et al. elegantly highlighted the point that “tissues harvested at revision surgery reflect specifically end-stage failure and may not adequately reveal the evolution of pathophysiological events that lead to osteolysis and prosthetic loosening ” [135]. To gain insight into the histomorphologic changes in tissue in well-fixed implants, Bos et al. did a cadaveric study of 25 prosthetic hip joints implanted for a mean of 7 (0.25–16) years [136]. Although these were cemented hip implants, and there was a contribution of both

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cement and UHMWPE wear debris, a timeline of changes within the surrounding tissue and bone was observed, as wear accumulation increased. In general, within a year of implantation, the initial granulation tissue was more fibrotic, and had increased in thickness. After 2.5 years, the number of histiocytes within the fibrous membrane dramatically increased concurrently with cement wear debris. This process did not plateau, but continued with increasing implant duration and the generation of UHMWPE wear debris. The histiocytes contained large amounts of phagocytosed wear debris, showed degenerative changes in chromatin structure and the disintegration of cell borders. In addition, giant cells were typically found around UHMWPE particles >30 mm. After 4 years of implantation, focal areas of necrosis were observed, which became large, confluent, and sharply delineated areas of necrosis by 5–7 years. A positive correlation with implant duration was found only for necrosis, although the increasing thickness of the fibrous tissue over time correlated with the increasing number of histiocytes and amount of wear debris. Necrosis may be caused by cell injury (e.g., ingestion of wear debris) or inflammation, and in turn necrotic cells release cellular contents that perpetuate and exacerbate inflammation and osteoclast mediated bone resorption (Figures 28.1 and 28.4). Morphologically, necrotic cells appear swollen and show signs of nuclear and cytoplasmic degeneration. Similar increases in histiocytes, wear debris accumulation, and necrosis were observed in three other cadaveric studies [29,137,138]. Inflammation, tissue damage, and decreased vascularization [22] can also instigate the conversion of fibrotic tissue to fibrocartilage and heterotopic ossification (bone formation in soft tissue that leads to the loss of tissue function). Formation of fibrocartilage changes the plasticity of the tissue and is an initial step toward heterotopic ossification, which has been observed in tissues around hip, knee, and spine implants. The

Figure 28.7 Other histomorphologic changes in periprosthetic hip tissue in response to gamma air-sterilized UHMWPE wear debris. (A) Representative regions of tissue calcification (green arrows), 15.6 years postimplantation; (B) Tissue necrosis with a few remaining intact cell nuclei, 19.7 years postimplantation. 100× magnification.

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formation of fibrocartilage may also occur in response to non-inflammatory events like micromotion of the implant [23]. Implant movement affects integrin and nonintegrin attachment of cells to extracellular matrix components, and as a result, adhesion–receptor signaling is modified, initiating transformation of fibrous tissue into fibrocartilage (metaplasia). The micro- and macromotion can also lead to ischemia–reperfusion injury of the vascular endothelial cell lining, decreasing vascularization of the tissue, and causing tissue hypoxia, tissue damage, and/or fibrocartilage formation [23]. The persistence of local inflammation, regardless of the number of years post initial surgery, and the development of fibrocartilage followed by heterotopic ossification has been observed in a number of other chronic inflammatory conditions that lead to the loss of tissue f­ unction [139–143]. The most obvious gross, clinical manifestation associated with wear particle generation is osteolysis, which has been identified as a major reason for implant loosening and the need for revision surgery after total hip replacement [1,23,24,26,27,30,93,144–149]. Current scientific theory still maintains that osteolysis around total joint replacements is governed by a “critical initiating event” of interaction between immune cells specialized to respond to foreign bodies and wear debris accumulation (e.g., monocytes/ macrophages/histiocytes) [26]. Evaluation of clinical data shows that patients revised for osteolysis consistently have UHMWPE particle quantities in the order of 10 billion particles per gram weight of tissue [150,151]. The accumulation of particles may be due to implant interface wear and/or micromotion of implant components with respect to each other (e.g., fretting) or with bone [147,152]. Both micron and submicron debris have been implicated as important contributors to the inflammatory response in periprosthetic tissue, and the onset of osteolysis (Figures 28.2, 28.3, and 28.5) [31,32,34]. Particleinduced osteolysis, or loss of bone around the implant, can lead to implant loosening due to the loss of implant fixation (bone–implant ingrowth). However, it is important to note that loosening may also occur due to inadequate initial fixation (fibrous tissue formation rather than bone ingrowth) or mechanical loss of fixation over time. Finally, UHMWPE wear particles can trigger type B synoviocytes in the surface layer of the pseudosynovial membrane to secrete more joint fluid into the joint space [153]. The resulting elevation in fluid pressure can lead to osteocyte (cells that control bone remodeling and bone formation) promotion of osteoclast differentiation and local periprosthetic bone resorption thereby

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promoting loosening at the bone–implant interface [23,154–157]. As a result of all of these potential mechanisms, mechanically loose prostheses undergo excessive displacement, subsidence and/or migration with the application of physiologic loads. Furthermore, monocytes/macrophages and dendritic cells in periprosthetic tissue have the potential to differentiate into fully functional osteoclasts capable of bone resorption [28,158–161]. Soluble products released by activated macrophages, dendritic cells, and fibroblasts in the periprosthetic tissue control the activity, proliferation, and differentiation of osteoclasts (Figure 28.4) [26,162–164]. Osteoclasts are formed from monocyte/macrophage precursors in response to RANKL and monocyte colony stimulating factor (M-CSF) release [165,166]. Osteoclast differentiation, fusion to form multinucleated cells and activation occur after the binding of RANKL to its receptor RANK. The relative expression of RANK, RANKL, and OPG, a molecule that competitively binds RANKL and thus prevents osteoclast activation, determines the amount of bone resorption at a given site. Specifically, the RANKL/OPG ratio is an important determinant of how much bone is resorbed. In addition, M-CSF and IL-1 are capable of acting directly on osteoclast precursors to promote osteoclast differentiation or indirectly by modulating RANKL and OPG expression. Bone resorption by osteoclasts includes degradation of the organic and inorganic parts of bone after differentiation and fusion, by creating a sealing zone between the bone and the osteoclast, into which protons, degradative enzymes (e.g., cathepsin K) and ROS by NOX2 and RNS by iNOS are released [26,47,48,51,167,168]. Proton pumps produce an acidic pH causing hydroxyapatite, the mineral making up the bone, to be dissolved and providing an environment that promotes proteolytic and ROS mediated bone resorption. The production of ROS and RNS can lead to oxidative stress (an imbalance between ROS production and removal that can activate cell signaling at low amounts or cause cell death at higher amounts) [62]. Low amounts of ROS trigger the upregulation of osteoinflammatory–oxidative stress responsive factors, which include high mobility group protein-B1 (HMGB1), COX2, iNOS, and the formation of ROS and RNS end products 4-hydroxynonenal (4-HNE) and nitrotyrosine (NT), respectively (Figure 28.2). Oxidative stress, at low concentrations of ROS, plays a role in promoting both osteoclast formation and osteoclast bone resorption, which can lead to osteolysis and potentially implant loosening [50,51,167,168]. In our recent study, the severity of osteolysis was shown to

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correlate with the amount of HMGB1 (a factor released by activated macrophages and cells undergoing necrosis that binds to TLR4 on macrophages to promote cell activation), 4-HNE accumulation and COX2 expression in periprosthetic tissues from gamma air-sterilized hip implants [51]. The accumulation of 4-HNE causes nuclear and cellular dysfunction, and COX2 produces products including PGE2 that are involved in promoting inflammation and an imbalance in osteoclast bone resorption and osteoblast bone formation, leading to bone loss. All of these factors are potential serum biomarkers for detecting early osteolysis after hip total joint replacement. Several other promising biomarkers for bone resorption have already been identified [14,169–171]. However, a panel rather than individual biomarkers will be required for early osteolysis detection.

28.7  Current Considerations Based on More Recent Findings and Approaches to Tissue Analysis Tissue, cellular, and molecular techniques, including histology, histochemistry, immunohistochemistry, in situ hybridization, polymerase chain reaction (PCR), Western and Northern blot, and single nucleotide polymorphism analysis, have yielded important information concerning the biologic processes in periprosthetic tissues [1,6,14,66,93,130,172,173]. However, many of the early studies evaluated the production of cytokines by cultured periprosthetic tissues [77]. The comparative findings of Shanbhag et al. shows that the protein profile is affected by placing the tissues in culture, and differs considerably from the cytokines, chemokines, and growth factors found in fresh tissue [134,144]. Using high throughput protein chips, this group analyzed 29 macrophage inflammation related cytokines, chemokines, and growth factors. Of the cytokines evaluated, freshly isolated tissue contained IL-6, IL-8, and chemoattractants for activated Th1 cells, but IL-1a, IL-1b, and TNF-a were not found in noncultured tissues from patients with end-stage osteolysis. The authors suggest that the presence of Th1 cell chemoattractants implies a role for these cells in the inflammatory process. IL-8 is produced by several cell types, and is chemotatic for T cells and neutrophils; it also promotes angiogenesis (blood vessel formation) and osteoclast differentiation [174,175]. Using real-time quantitative PCR, others have detected the

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presence of alternative M2 activation markers, IL-8, and MIP-1a, increased markers of osteoclast differentiation, decreased local OPG levels and reduced expression of osteogenesis factors [130,134,144]. The inconsistency between studies can be attributed to variable approaches in measuring tissue factors, duration of implantation, and the reasons for revision. Although gains have been made, standardization of methods for analyzing tissue responses is necessary in order to compare data across multiple studies to obtain a consensus of the results. For example, Phillips et al. compared two established but highly divergent scoring methods for histological analysis of periprosthetic tissues from metal-on-metal revision patients [176–178]. Based on this study, the Oxford scoring system, developed by Grammatopoulos et al., is better suited for scoring nonspecific foreign-body macrophage responses, perivascular lymphocytic infiltration, and necrosis [177]. The Oxford system is also suitable for scoring morphological changes in tissues that contain UHMWPE wear particles, since macrophages are the primary immune cells involved in particle phagocytosis and subsequent tissue necrosis [176]. Thus, the Oxford scoring system provides a straightforward and reproducible way of reporting tissue responses for all artificial joint replacements revised for wear debris, loosening, fracture or ­malposition.

28.8  Exacerbation of the Immune Response to Wear Debris as a Result of Subclinical Infection One of the commonly overlooked reasons for implant loosening and revision surgery for well-fixed implants is subclinical infection [179–181]. The major reason for this oversight is that subclinical infection is very difficult to diagnose. When infection is suspected in revision cases, clinical laboratory tests are performed, which include a joint aspirate for bacterial culture, white blood cell (WBC) count and a differential, and a peripheral blood draw for erythrocyte sedimentation rate (ESR), WBC count and differential, and serum levels of C-reactive protein [182]. However, all of the current approaches, including bacterial cultures and PCR to detect various bacterial species have so far proved to be inadequate [183–185]. Nonetheless, newer research using PCRbased electron spray ionization time-of-flight mass spectrometry (ESI-TOF-MS) has shown promise in diagnosing both subclinical and septic joint infections

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[181]. In addition, other recent studies have explored the potential use of synovial fluid biomarkers as valid diagnostic tools for the presence of periprosthetic infection. Deirmengian et al. identified five biomarkers, including human a-defensin 1–3, neutrophil elastase 2, bactericidal–permeability-increasing protein, neutrophil gelatinase-associated lipocalin, and lactoferrin, that have the potential to accurately predict periprosthetic joint infection [186–188]. Further studies will be necessary to determine if these or other biomarkers can be used to diagnose subclinical infections that may not be directly involved in clinical joint failure but may contribute to macrophage activation, osteoclast formation, and osteolysis. Based on the evaluation of periprosthetic tissues which are obtained at the time of revision surgery, Schroeder, et al. established a histomorphological criteria, in conjunction with polarized light microscopy, to define four types of periprosthetic membranes: membranes with wear debris (type I), those with infection based on the numbers of neutrophils responding to the presence of bacteria (type II), combined types I and II (type III) and periprosthetic membranes with no obvious wear debris or infection (type IV) [180]. Most notable was that the four types of periprosthetic membranes were observed at significantly different times of revision. This new classification system provides a more standardized diagnostic approach to determine the etiology and pathophysiology of THR revisions [189,190]. However, it does not provide a scoring system for specific tissue changes that would allow multiple study result comparisons provided by other groups [176–178]. Although subclinical joint infection may not lead to clinical joint failure, it can enhance the activation of macrophages. This occurs in response to several bacterial products, lipopolysacchride (LPS, gram negative bacteria), lipoteichoic acid, and peptidoglycan (gram positive bacteria) [185]. LPS, also known as endotoxin, has been identified in periprosthetic tissue homogenates from failed joint replacements, even when signs of clinical infections were absent [191–194]. Endotoxins can adhere to both polyethylene and metal wear debris in vivo, which can then enhance the phagocytosis of particles (via TLR4 binding), osteoclast formation, bone resorption, and contribute to wear-induced bone loss [195–198]. In vitro, endotoxin adsorbed onto polyethylene particles strongly promotes the production of proinflammatory cytokines [199,200]. Therefore, the presence of subclinical infections has the potential to greatly increase the host response to the generation of wear debris. In addition, the presence of bacterial p­ roducts

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on wear particles may reduce the threshold required for the initiation of pathophysiologic changes in periprosthetic tissue and bone. Future studies are required to determine how subclinical infection exacerbates wear debris mediated osteolysis and whether treatment is warranted.

28.9  HXLPE and Histopathophysiologic Changes in Periprosthetic Hip Tissues from Implant Retrievals Highly crosslinked UHMWPE (HXLPE) was clinically introduced in 1998 to reduce implant wear, wear debris generation, inflammation, and osteolysis. A number of clinical reports provide evidence that the use of HXLPE has indeed decreased implant volumetric wear [201–203]. However, the reduced risk of osteolysis when compared to conventional UHMWPE is somewhat controversial. Despite numerous reports suggesting osteolysis in not a major contributing factor, one group reported that 10 out of 39 patients (26%) with HXLPE liners that required revision surgery showed signs of radiographic osteolysis as early as five years post implantation [204]. In two separate studies that used computed tomography (CT) to detect osteolytic lesions, which has much greater sensitivity than plain radiographs, 2–8% of patients with HXLPE hip liners showed signs of osteolysis at 5–6 years postimplantation [205,206]. Thus, even in the absence of significant HXLPE liner wear, osteolysis is detected before revision (CT) and at the time of revision surgery. Furthermore, in vitro studies have suggested that wear particles generated from HXLPE material may cause an increased biological response, which despite a low wear rate, may lead to osteolysis (Endo et al., 2002; Ingram et al., 2004). Specifically, HXLPE particles induced an increased release of macrophage proinflammatory cytokines compared to conventional UHMWPE particles (Ingram et al., 2004). Furthermore, although wear simulator studies show that HXLPE material produces fewer particles overall, the relative percentage of small wear particles in the most biologically active or proinflammatory 0.1–1.0 size range is higher (Endo et al., 2002). Preliminary animal studies are comparable with the increased inflammation observed in response to HXLPE particles in vitro [207,208]. Literature reviews of previous periprosthetic tissue studies suggest that the particle characteristics of

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HXLPE may not eliminate the biological response, and the reduction in wear of HXLPE liners does not directly relate with a decrease in periprosthetic osteolysis [209–211]. However, periprosthetic tissue studies for HXLPE revisions are extremely limited compared to tissues retrieved from patients receiving gamma air-sterilized or conventional UHMWPE components. To provide a context of differences between the osteolytic potential of wear debris from gamma air-sterilized UHMWPE and gamma inertsterilized HXLPE materials, we compared histopathologic changes in periprosthetic tissues from primary total hip revision surgery [212]. Unfortunately, as gamma air-sterilized UHMWPE material is no longer used, the retrieved components had significantly longer implantation times as compared to the HXLPE components. While this is of concern, we believe that providing a context related to differences in the tissue responses at the time of revision is valuable in obtaining a better understanding of implant longevity. We found more prevalent and extensive inflammation, histiocytosis, necrosis, and wear debris in tissues retrieved from gamma air-sterilized UHMWPE hip implants (seven out of nine patients). The presence of inflammation and histiocytes correlated with the accumulation of small UHMWPE wear debris (0.5–2 mm), and giant cells were consistently found near large UHMWPE particles (>10 mm). In addition, the presence of histiocytes and small wear debris correlated with focal regions of tissue necrosis. Findings for the gamma air-sterilized patient group are in agreement with those reported by others and are consistent with an inflammatory-mediated response to UHMWPE wear particles [213–215]. Collectively, these histomorphological changes can contribute to tissue dysfunction, pain, osteolysis, and implant loosening. For the HXLPE cohort of patients, histiocytes, and associated small wear debris were limited, and only four out of nine patient tissues had signs of inflammation. For patients revised before two years, inflammation was not detected and large amounts of fibrocartilage/bone were frequently observed within the tissue, suggesting that micromotion of the femoral stem may contribute to fibrocartilage formation. None of these patients were revised for radiographic osteolysis, although proximal femoral tissue was obtained from three patients and retroacetabular tissue from two patients, suggesting that radiographic osteolysis may have been inadequate to detect bone loss in these patients. For both cohorts, these regions contained the most wear debris, inflammation, and necrosis.

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As a follow up to the original study, we used immunohistochemistry to evaluate the contribution of the innate and adaptive immune responses in tissues for both cohorts [216]. For the innate response, the number of neutrophils (MPO) and macrophages (CD68) (Figure 28.3) were determined and for the adaptive response, T lymphocytes (CD3) were counted (Figure 28.5). For the gamma air-sterilized cohort, correlations were observed between wear debris and the magnitude of individual patient macrophage and T cell responses, and between numbers of macrophages and T cells in periprosthetic tissues. In comparison, the HXLPE cohort showed a correlation between wear debris and the magnitude of macrophage responses, and between the number of macrophages and T cells. Although macrophages and T cells were present in both cohorts, the HXLPE patients had lower numbers of inflammatory cells and as mentioned earlier, significantly less wear debris within the ≥0.5 mm range. None of the patient tissues contained enough neutrophils to indicate a subclinical infection. In a case study of two patients that received HXLPE hip implants, Knahr et al. reported the presence of macrophages, a few lymphocytes and giant cells in the pseudocapsular tissues, but very limited amounts of wear particles [217]. Our findings are similar in that macrophages were the predominant inflammatory cells and there was limited wear debris. The limitations of the Knahr et al. study were that immunohistochemistry to identify the inflammatory cells and wear particle characterization were not performed. In a separate study, the differences in size, shape, number, and biological activity of UHMWPE wear particles isolated from periprosthetic hip tissues were compared for implants with gamma-inert sterilized conventional UHMWPE and remelted or annealed HXLPE liners. Based on environmental scanning electron microscope analysis, the total number of wear particles were lower in tissues from both HXLPE cohorts, however, both contained an increased percentage of submicron particles (<1.0 mm) compared to the conventional UHMWPE cohort [218]. Consistent with our findings, Minoda et al. also reported that HXLPE resulted in less, smaller, and rounder particles in a case study of a patient that received a HXLPE hip implant [219]. These particles have been reported to stimulate an increased production of proinflammatory cytokines compared to particles >1.0 mm [97,99]. The presence of submicron particles is consistent with the observation that histiocytes and macrophages were present in tissues from the HXLPE cohort and yet limited amounts of

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wear debris were detected, as the size limitation in our earlier studies was 0.5 mm [212,216]. It is important to note that the specific biological activity for the HXLPE particles was increased compared to the conventional UHMWPE particles. However, based on the decreased number of HXLPE wear particles there was a significant decrease in total particle volume (millimeter cube per gram of tissue). Accordingly, when the specific biological activity was normalized by total particle volume or by component wear volume rate (millimeter cube per year), functional biological activity of the HXLPE wear debris was significantly lower compared to the conventional gamma-inert sterilized cohort wear debris. However, the majority of these patients were revised within the first 3 years post implantation and long term studies are required to adequately assess the osteolytic potential of HXLPE wear debris. The current findings suggest that wear debris-induced inflammation may be a major contributor to the loss of implant function for historical gamma airsterilized and gamma-inert sterilized conventional UHMWPE hip implant patients, but it may not be the primary cause of early implant loosening for the HXLPE cohort. Nonetheless, poor implant osseointegration and/or mechanical factors based on the stiffness of this material may still contribute to implant loosening of HXLPE hip implants and result in the need for revision surgery. Information on the tissue response and particle characteristics, for the most part, are based on our studies (Baxter et al.), hence there remains a shortage of information on periprosthetic tissue reactions to HXLPE particles. As periprosthetic tissue from revised HXLPE components are retrieved with increasing times of implantation, we and others will have the opportunity to compare early and late pathophysiologic responses, providing more conclusive answers to the question of whether submicron wear debris accumulation over time will contribute to osteolysis for this implant liner material.

28.10 Conclusions This chapter summarizes the current understanding of both the inflammatory and histomorphologic related tissue changes that result from the generation of UHMWPE wear debris. The overall tissue response to wear debris remains both complex and patient-specific. Nonetheless, the limitations of earlier methods of tissue preservation and in vitro and in vivo model systems are being increasingly recognized and improved. In addition, technological

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methods for tissue analysis are continually being updated, such as single nucleotide polymorphisms to detect genetic variability among patients and the use of protein microarrays to measure specific profiles of proteins and cell signaling factors. With new technological advances, and increased implantation time comparisons for HXLPE components, an improved understanding of regional and systemic immune responses to UHMWPE wear debris will continue to evolve. Ultimately, a better understanding of these processes will not only help identify risks associated with current implant materials and designs, it will also provide insight into the early diagnosis and treatment of inflammatory mechanisms and subclinical infections involved in the loss of implant function. It is therefore imperative that tissue and genetic analyses continue to be performed to ensure future implant technology provides the most biologically compatible material, optimal design and most importantly, implant longevity.

Acknowledgments The information provided in this chapter was supported by grants from the NIH: R01 AR47904 and R01 AR56264. We would also like to thank Dr Ryan Baxter and Dr Theresa Freeman for their help in putting together the information for this chapter.

References [1] S. Goodman, Wear particulate and osteolysis, Orthop. Clin. North Am. 36 (2005) 41–48. [2] H.G. Willert, Reactions of the articular capsule to wear products of artificial joint prostheses, J. Biomed. Mater. Res. A 11 (1977) 157–164. [3] P. Aspenberg, H. Van der Vis, Migration, particles, and fluid pressure. A discussion of causes of prosthetic loosening, Clin. Orthop. Relat. Res. (352) (1998) 75–80. [4] R.M. Urban, J.J. Jacobs, M.J. Tomlinson, J. Gavrilovic, J. Black, M. Peoc’h, Dissemination of wear particles to the liver, spleen, and abdominal lymph nodes of patients with hip or knee replacement, J. Bone Joint Surg. Am. 82 (2000) 457–476. [5] M.H. Gray, M.L. Talbert, W.M. Talbert, M. Bansal, A. Hsu, Changes seen in lymph nodes draining the sites of large joint prostheses, Am. J. Surg. Pathol. 13 (1989) 1050–1056. [6] D.G. Hicks, A.R. Judkins, J.Z. Sickel, R.N. Rosier, J.E. Puzas, R.J. O’Keefe, Granular

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histiocytosis of pelvic lymph nodes following total hip arthroplasty. The presence of wear debris, cytokine production, and immunologically activated macrophages, J. Bone Joint Surg. Am. 78 (1996) 482–496. [7] M.H.A. Malik, F. Jury, A. Bayat, W.E.R. Ollier, P.R. Kay, Genetic susceptibility to total hip arthroplasty failure: a preliminary study on the influence of matrix metalloproteinase 1, interleukin 6 polymorphisms and vitamin D receptor, Ann. Rheum. Dis. 66 (2007) 1116–1120. [8] J.M. Wilkinson, A.G. Wilson, I. Stockley, I.R. Scott, D.A. Macdonald, A.J. Hamer, et al. Variation in the TNF gene promoter and risk of osteolysis after total hip arthroplasty, J. Bone Miner. Res. 18 (2003) 1995–2001. [9] S.J. MacInnes, E.D. Vescovo, E. Kiss-Toth, W.E. Ollier, P.R. Kay, A. Gordon, et al. Genetic variation in inflammatory and bone turnover pathways and risk of osteolytic responses to prosthetic materials, J. Orthop. Res. 33 (2015) 193–198. [10] R. Kolundzic, D. Orlic, V. Trkulja, K. Pavelic, K.G. Troselj, Single nucleotide polymorphisms in the interleukin-6 gene promoter, tumor necrosis factor-alpha gene promoter, and transforming growth factor-beta1 gene signal sequence as predictors of time to onset of aseptic loosening after total hip arthroplasty: preliminary study, J. Orthop. Sci. 11 (2006) 592–600. [11] J. Gallo, F. Mrazek, M. Petrek, Variation in cytokine genes can contribute to severity of acetabular osteolysis and risk for revision in patients with ABG 1 total hip arthroplasty: a genetic association study, BMC Med. Genet. 10 (2009) 109. [12] A. Gordon, E. Kiss-Toth, I. Stockley, R. Eastell, J.M. Wilkinson, Polymorphisms in the interleukin-1 receptor antagonist and interleukin-6 genes affect risk of osteolysis in patients with total hip arthroplasty, Arthritis. Rheum. 58 (2008) 3157–3165. [13] R.L. Smith, E.M. Schwarz, Are biologic treatments a potential approach to wear- and corrosion-related problems?, Clin. Orthop. Relat. Res. 472 (12) (2014) 3740–3746. [14] D.R. Sumner, R. Ross, E. Purdue, Are there biological markers for wear or corrosion? A systematic review, Clin. Orthop. Relat. Res. 472 (12) (2014) 3728–3739. [15] T.W. Bauer, A.S. Shanbhag, Implant wear symposium biologic work G. Are there biolog-

521

ical markers of wear?, J. Am. Acad. Orthop. Surg. 16 (Suppl. 1) (2008) S68–S71. [16] P.E. William, Fundamental Immunology, sixth ed., Wolters Kluwer/Lippincott Williams & Wilkins, Philadelphia, 2008. [17] M. Akdis, S. Burgler, R. Crameri, T. Eiwegger, H. Fujita, E. Gomez, et al. Interleukins, from 1 to 37, and interferon-gamma: receptors, functions, and roles in diseases, J. Allergy Clin. Immunol. 127 (2011) 701–721 e1-e70. [18] S. Santavirta, J.W. Xu, J. Hietanen, A. Ceponis, T. Sorsa, R. Kontio, et al. Activation of periprosthetic connective tissue in aseptic loosening of total hip replacements, Clin. Orthop. Relat. Res. (352) (1998) 16–24. [19] S.R. Goldring, A.L. Schiller, M. Roelke, C.M. Rourke, D.A. O’Neil, W.H. Harris, The synovial-like membrane at the bone-cement interface in loose total hip replacements and its proposed role in bone lysis, J. Bone Joint Surg. Am. 65 (1983) 575–584. [20] S.R. Goldring, M. Jasty, M.S. Roelke, C.M. Rourke, F.R. Bringhurst, W.H. Harris, Formation of a synovial-like membrane at the bonecement interface. Its role in bone resorption and implant loosening after total hip replacement, Arthritis Rheum. 29 (1986) 836–842. [21] S.B. Goodman, R.C. Chin, S.S. Chiou, D.J. Schurman, S.T. Woolson, M.P. Masada, A clinical-pathologic-biochemical study of the membrane surrounding loosened and nonloosened total hip arthroplasties, Clin. Orthop. (1989) 182–187. [22] J. Gallo, P. Kaminek, V. Ticha, P. Rihakova, R. Ditmar, Particle disease. A comprehensive theory of periprosthetic osteolysis: a review, Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech. Repub. 146 (2002) 21–28. [23] Y.T. Konttinen, D. Zhao, A. Beklen, G. Ma, M. Takagi, M. Kivela-Rajamaki, et al. The microenvironment around total hip replacement prostheses, Clin. Orthop. (2005) 28–38. [24] H.G. Willert, H. Bertram, G.H. Buchhorn, Osteolysis in alloarthroplasty of the hip. The role of ultra-high molecular weight polyethylene wear particles, Clin. Orthop. (1990) 95–107. [25] R. Maitra, C.C. Clement, B. Scharf, G.M. Crisi, S. Chitta, D. Paget, et al. Endosomal damage and TLR2 mediated inflammasome activation by alkane particles in the generation of aseptic osteolysis, Mol. Immunol. 47 (2009) 175–184. [26] P.E. Purdue, P. Koulouvaris, H.G. Potter, B.J. Nestor, T.P. Sculco, The cellular and molecular

522

biology of periprosthetic osteolysis, Clin. Orthop. 454 (2007) 251–261. [27] Y. Abu-Amer, I. Darwech, J.C. Clohisy, Aseptic loosening of total joint replacements: mechanisms underlying osteolysis and potential therapies, Arthritis Res. Ther. 9 (Suppl. 1) (2007) S6. [28] R. Maitra, A. Follenzi, A. Yaghoobian, C. Montagna, S. Merlin, E.S. Cannizzo, et al. Dendritic cell-mediated in vivo bone resorption, J. Immunol. 185 (2010) 1485–1491. [29] S. Santavirta, Y.T. Konttinen, V. Bergroth, A. Eskola, K. Tallroth, T.S. Lindholm, Aggressive granulomatous lesions associated with hip arthroplasty. Immunopathological studies, J. Bone Joint Surg. Am. 72 (1990) 252–258. [30] P.A. Revell, The combined role of wear particles, macrophages and lymphocytes in the loosening of total joint prostheses, J. R. Soc. Interface 5 (2008) 1263–1278. [31] T.P. Schmalzried, P. Campbell, A.K. Schmitt, I.C. Brown, H.C. Amstutz, Shapes and dimensional characteristics of polyethylene wear particles generated in vivo by total knee replacements compared to total hip replacements, J. Biomed. Mater. Res. 38 (1997) 203–210. [32] A.S. Shanbhag, H.O. Bailey, D.S. Hwang, C.W. Cha, N.G. Eror, H.E. Rubash, Quantitative analysis of ultrahigh molecular weight polyethylene (UHMWPE) wear debris associated with total knee replacements, J. Biomed. Mater. Res. 53 (2000) 100–110. [33] L. Richards, C. Brown, M.H. Stone, J. Fisher, E. Ingham, J.L. Tipper, Identification of nanometre-sized ultra-high molecular weight polyethylene wear particles in samples retrieved in vivo, J. Bone Joint Surg. Br. 90 (2008) 1106– 1113. [34] J.L. Tipper, E. Ingham, J.L. Hailey, A.A. Besong, J. Fisher, B.M. Wroblewski, et al. Quantitative analysis of polyethylene wear debris, wear rate and head damage in retrieved Charnley hip prostheses, J. Mater. Sci. Mater. Med. 11 (2000) 117–124. [35] A.P.D. Elfick, S.M. Green, S. Krikler, A. Unsworth, The nature and dissemination of UHMWPE wear debris retrieved from periprosthetic tissue of THR, J. Biomed. Mater. Res. 65A (2003) 95–108. [36] T.P. Schmalzried, P. Campbell, Isolation and characterization of debris in membranes around total joint prostheses, J. Bone Joint Surg. Am. 77 (1995) 1625–1626.

UHMWPE Biomaterials Handbook

[37] P. Campbell, S. Ma, B. Yeom, H. McKellop, T.P. Schmalzried, H.C. Amstutz, Isolation of predominantly submicron-sized UHMWPE wear particles from periprosthetic tissues, J. Biomed. Mater. Res. 29 (1995) 127–131. [38] W.J. Maloney, R.L. Smith, T.P. Schmalzried, J. Chiba, D. Huene, H. Rubash, Isolation and characterization of wear particles generated in patients who have had failure of a hip arthroplasty without cement, J. Bone Joint Surg. Am. 77 (1995) 1301–1310. [39] K.J. Margevicius, T.W. Bauer, J.T. McMahon, S.A. Brown, K. Merritt, Isolation and characterization of debris in membranes around total joint prostheses, J. Bone Joint Surg. Am. 76 (1994) 1664–1675. [40] P. Drees, A. Eckardt, R.E. Gay, S. Gay, L.C. Huber, Mechanisms of disease: molecular insights into aseptic loosening of orthopedic implants, Nat. Clin. Pract. Rheumatol. 3 (2007) 165–171. [41] K. Hirota, H. Terada, Endocytosis of particle formulations by macrophages and its application to clinical treatment, in: B. Ceresa (Ed.), Molecular Regulation of Endocytosis, InTech, Rijeka, Croatia, 2012, pp. 413–428. [42] N.J. Hallab, J.J. Jacobs, Biologic effects of implant debris, Bull. NYU Hosp. Jt. Dis. 67 (2009) 182–188. [43] M.K. Pratten, J.B. Lloyd, Pinocytosis and phagocytosis: the effect of size of a particulate substrate on its mode of capture by rat peritoneal macrophages cultured in vitro, Biochim. Biophys. Acta 881 (1986) 307–313. [44] N. Cobelli, B. Scharf, G.M. Crisi, J. Hardin, L. Santambrogio, Mediators of the inflammatory response to joint replacement devices, Nat. Rev. Rheumatol. 7 (2011) 600–608. [45] Q-h Jin, H-s Lu, Z-k Chen, D-f Jiang, Y-h. Wang, Significance and role of increased expression of extracellular matrix metalloproteinase induced in the aseptic loosening of prostheses, Chung Hua Wai Ko Tsa Chih 42 (2004) 1232–1235. [46] Q. Qi, M. Dai, X. Dong, Influence and role of expression of extracellular matrix metalloproteinase inducer and matrix metalloproteinase 9 in aseptic loosening of prosthesis, Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 27 (2013) 1175–1180. [47] S.A. Syggelos, A.J. Aletras, I. Smirlaki, S.S. Skandalis, Extracellular matrix degradation and tissue remodeling in periprosthetic loosening and osteolysis: focus on matrix

28:  Pathophysiologic Reactions to UHMWPE Wear Particles

metalloproteinases, their endogenous tissue inhibitors, and the proteasome, Biomed. Res. Int. 2013 (2013) 230805. [48] M. Takagi, S. Santavirta, H. Ida, M. Ishii, J. Mandelin, Y.T. Konttinen, Matrix metalloproteinases and tissue inhibitors of metalloproteinases in loose artificial hip joints, Clin. Orthop. (1998) 35–45. [49] M.L. Wang, P.F. Sharkey, R.S. Tuan, Particle bioreactivity and wear-mediated osteolysis, J. Arthroplasty 19 (2004) 1028–1038. [50] P. Kinov, P. Tivchev, Evidence linking elevated oxidative stress and aseptic loosening of hip arthroplasty, in: S.K. Fokter (Ed.), Recent Advances in Arthroplasty, InTech, Rijeka, Croatia, 2012, pp. 295–318. [51] M.J. Steinbeck, L.J. Jablonowski, J. Parvizi, T.A. Freeman, The role of oxidative stress in aseptic loosening of total hip arthroplasties, J. Arthroplasty 29 (2014) 843–849. [52] L.A. O’Neill, Immunology. How frustration leads to inflammation, Science 320 (2008) 619–620. [53] B.M. Babior, Oxygen-dependent microbial killing by phagocytes (second of two parts), N. Engl. J. Med. 298 (1978) 721–725. [54] B.M. Babior, Superoxide: a two-edged sword, Braz. J. Med. Biol. Res. 30 (1997) 141–155. [55] B.M. Babior, Phagocytes and oxidative stress, Am. J. Med. 109 (2000) 33–44. [56] U. Forstermann, H.H. Schmidt, K.L. Kohlhaas, F. Murad, Induced RAW 264.7 macrophages express soluble and particulate nitric oxide synthase: inhibition by transforming growth factorbeta, Eur. J. Pharmacol. 225 (1992) 161–165. [57] C.F. Nathan, D.J. Stuehr, Does endotheliumderived nitric oxide have a role in cytokineinduced hypotension?, J. Natl. Cancer Inst. 82 (1990) 726–728. [58] S. Moncada, R.M. Palmer, E.A. Higgs, Biosynthesis of nitric oxide from L-arginine. A pathway for the regulation of cell function and communication, Biochem. Pharmacol. 38 (1989) 1709–1715. [59] K.L. Davis, E. Martin, I.V. Turko, F. Murad, Novel effects of nitric oxide, Annu. Rev. Pharmacol. Toxicol. 41 (2001) 203–236. [60] R.F. Furchgott, Endothelium-derived relaxing factor: discovery, early studies, and identification as nitric oxide, Biosci. Rep. 19 (1999) 235–251. [61] B.M. Babior, Oxidants from phagocytes: agents of defense and destruction, Blood 64 (1984) 959–966.

523

[62] B. Halliwell, Phagocyte-derived reactive species: salvation or suicide?, Trends Biochem. Sci. 31 (2006) 509–515. [63] L.J. Ignarro, Haem-dependent activation of guanylate cyclase and cyclic GMP formation by endogenous nitric oxide: a unique transduction mechanism for transcellular signaling, Pharmacol. Toxicol. 67 (1990) 1–7. [64] S.A. Solovieva, A. Ceponis, Y.T. Konttinen, M. Takagi, A. Suda, K.K. Eklund, et al. Mast cells in loosening of totally replaced hips, Clin. Orthop. (1996) 158–165. [65] J. Qiu, M.J. Beckman, J. Qian, W. Jiranek, Simultaneous labeling of mast cell proteases and protease mRNAs at the bone-implant interface of aseptically loosened hip implants, J. Orthop. Res. 23 (2005) 942–948. [66] E.M. Greenfield, Do genetic susceptibility, tolllike receptors, and pathogen-associated molecular patterns modulate the effects of wear?, Clin. Orthop. Relat. Res. 472 (12) (2014) 3709–3717. [67] R. Maitra, C.C. Clement, G.M. Crisi, N. Cobelli, L. Santambrogio, Immunogenecity of modified alkane polymers is mediated through TLR1/2 activation, PLoS One 3 (2008) e2438. [68] T. Lahdeoja, J. Pajarinen, V.P. Kouri, T. Sillat, J. Salo, Y.T. Konttinen, Toll-like receptors and aseptic loosening of hip endoprosthesis-a potential to respond against danger signals?, J. Orthop. Res. 28 (2010) 184–190. [69] J. Pajarinen, E. Cenni, L. Savarino, E. GomezBarrena, Y. Tamaki, M. Takagi, et al. Profile of toll-like receptor-positive cells in septic and aseptic loosening of total hip arthroplasty implants, J. Biomed. Mater. Res. A 94 (2010) 84–92. [70] M. Takagi, Y. Tamaki, H. Hasegawa, Y. Takakubo, L. Konttinen, V.M. Tiainen, et al. Toll-like receptors in the interface membrane around loosening total hip replacement implants, J. Biomed. Mater. Res. A 81 (2007) 1017–1026. [71] Y. Tamaki, Y. Takakubo, K. Goto, T. Hirayama, K. Sasaki, Y.T. Konttinen, et al. Increased expression of toll-like receptors in aseptic loose periprosthetic tissues and septic synovial membranes around total hip implants, J. Rheumatol. 36 (2009) 598–608. [72] D.S. Rakshit, J.T.E. Lim, K. Ly, L.B. Ivashkiv, B.J. Nestor, T.P. Sculco, et al. Involvement of complement receptor 3 (CR3) and scavenger receptor in macrophage responses to wear debris, J. Orthop. Res. 24 (2006) 2036–2044.

524

[73] S.L. Deshmane, S. Kremlev, S. Amini, B.E. Sawaya, Monocyte chemoattractant protein-1 (MCP-1): an overview, J. Interferon Cytokine Res. 29 (2009) 313–326. [74] A.E. Proudfoot, C.A. Power, T.N. Wells, The strategy of blocking the chemokine system to combat disease, Immunol. Rev. 177 (2000) 246–256. [75] J. Chiba, L.J. Schwendeman, R.E. Booth Jr., L.S. Crossett, H.E. Rubash, A biochemical, histologic, and immunohistologic analysis of membranes obtained from failed cemented and cementless total knee arthroplasty, Clin. Orthop. (1994) 114–124. [76] W.A. Jiranek, M. Machado, M. Jasty, D. Jevsevar, H.J. Wolfe, S.R. Goldring, et al. Production of cytokines around loosened cemented acetabular components. Analysis with immunohistochemical techniques and in situ hybridization, J. Bone Joint Surg. Am. 75 (1993) 863–879. [77] A.S. Shanbhag, J.J. Jacobs, J. Black, J.O. Galante, T.T. Glant, Cellular mediators secreted by interfacial membranes obtained at revision total hip arthroplasty, J. Arthroplasty 10 (1995) 498–506. [78] M. Hukkanen, S.A. Corbett, J. Batten, Y.T. Konttinen, I.D. McCarthy, J. Maclouf, et al. Aseptic loosening of total hip replacement. Macrophage expression of inducible nitric oxide synthase and cyclo-oxygenase-2, together with peroxynitrite formation, as a possible mechanism for early prosthesis failure, J. Bone Joint Surg. Br. 79 (1997) 467–474. [79] F. Yang, W. Wu, L. Cao, Y. Huang, Z. Zhu, T. Tang, et al. Pathways of macrophage apoptosis within the interface membrane in aseptic loosening of prostheses, Biomaterials 32 (2011) 9159–9167. [80] A. Arora, Y. Song, L. Chun, P. Huie, M. Trindade, R.L. Smith, et al. The role of the TH1 and TH2 immune responses in loosening and osteolysis of cemented total hip replacements, J. Biomed. Mater. Res. A 64 (2003) 693–697. [81] A. Farber, R. Chin, Y. Song, P. Huie, S. Goodman, Chronic antigen-specific immune-system activation may potentially be involved in the loosening of cemented acetabular components, J. Biomed. Mater. Res. 55 (2001) 433–441. [82] D.H. DeHeer, J.A. Engels, A.S. DeVries, R.H. Knapp, J.D. Beebe, In situ complement activation by polyethylene wear debris, J. Biomed. Mater. Res. A 54 (2001) 12–19.

UHMWPE Biomaterials Handbook

[83] P.H. Wooley, R.H. Fitzgerald Jr., Z. Song, P. Davis, J.D. Whalen, S. Trumble, et al. Proteins bound to polyethylene components in patients who have aseptic loosening after total joint arthroplasty. A preliminary report., J. Bone Joint Surg. Am. 81 (1999) 616–623. [84] T.A. Freeman, J. Parvizi, C.J. Della Valle, M.J. Steinbeck, Reactive oxygen and nitrogen species induce protein and DNA modifications driving arthrofibrosis following total knee arthroplasty, Fibrogenesis Tissue Repair 2 (2009) 5. [85] E. Bettelli, V.K. Kuchroo, IL-12- and IL23-induced T helper cell subsets: birds of the same feather flock together, J. Exp. Med. 201 (2005) 169–171. [86] J.K. Kolls, A. Linden, Interleukin-17 family members and inflammation, Immunity 21 (2004) 467–476. [87] P. Miossec, Interleukin-17 in rheumatoid arthritis: if T cells were to contribute to inflammation and destruction through synergy, Arthritis Rheum. 48 (2003) 594–601. [88] Y.T. Konttinen, T.F. Li, J.W. Xu, M. Takagi, L. Pirilä, T. Silvennoinen, et al. Expression of laminins and their integrin receptors in different conditions of synovial membrane and synovial membrane-like interface tissue, Ann. Rheum. Dis. 58 (1999) 683–690. [89] R.S. Huss, J.I. Huddleston, S.B. Goodman, E.C. Butcher, B.A. Zabel, Synovial tissueinfiltrating natural killer cells in osteoarthritis and periprosthetic inflammation, Arthritis Rheum. 62 (2010) 3799–3805. [90] J.K. Antonios, Z. Yao, C. Li, A.J. Rao, S.B. Goodman, Macrophage polarization in response to wear particles in vitro, Cell Mol. Immunol. 10 (2013) 471–482. [91] T.H. Lin, S. Kao, T. Sato, J. Pajarinen, R. Zhang, F. Loi, et al. Exposure of polyethylene particles induces interferon-gamma expression in a natural killer T lymphocyte and dendritic cell coculture system in vitro: a preliminary study, J. Biomed. Mater. Res. A 103 (2014) 71–75. [92] A.J. Rao, C. Nich, L.S. Dhulipala, E. Gibon, R. Valladares, S. Zwingenberger, et al. Local effect of IL-4 delivery on polyethylene particle induced osteolysis in the murine calvarium, J. Biomed. Mater. Res. A 101 (2013) 1926–1934. [93] J. Gallo, S.B. Goodman, Y.T. Konttinen, M. Raska, Particle disease: biologic mechanisms of periprosthetic osteolysis in total hip arthroplasty, Innate. Immun. 19 (2013) 213–224.

28:  Pathophysiologic Reactions to UHMWPE Wear Particles

[94] S.C. O’Neill, J.M. Queally, B.M. Devitt, P.P. Doran, J.M. O’Byrne, The role of osteoblasts in peri-prosthetic osteolysis, Bone Joint J. 95B (2013) 1022–1026. [95] R. Chiu, T. Ma, R.L. Smith, S.B. Goodman, Ultrahigh molecular weight polyethylene wear debris inhibits osteoprogenitor proliferation and differentiation in vitro, J. Biomed. Mater. Res. A 89 (2009) 242–247. [96] T.R. Green, J. Fisher, J.B. Matthews, M.H. Stone, E. Ingham, Effect of size and dose on bone resorption activity of macrophages by in vitro clinically relevant ultra high molecular weight polyethylene particles, J. Biomed. Mater. Res. 53 (2000) 490–497. [97] T.R. Green, J. Fisher, M. Stone, B.M. Wroblewski, E. Ingham, Polyethylene particles of a ’critical size’ are necessary for the induction of cytokines by macrophages in vitro, Biomaterials 19 (1998) 2297–2302. [98] E. Ingham, J. Fisher, Biological reactions to wear debris in total joint replacement, Proc. Inst. Mech. Eng. H 214 (2000) 21–37. [99] J. Fisher, J. Bell, P.S. Barbour, J.L. Tipper, J.B. Matthews, A.A. Besong, et al. A novel method for the prediction of functional biological activity of polyethylene wear debris, Proc.Inst. Mech. Eng. H 215 (2001) 127–132. [100] D.R. Haynes, S.J. Boyle, S.D. Rogers, D.W. Howie, B. Vernon-Roberts, Variation in cytokines induced by particles from different prosthetic materials, Clin. Orthop. (1998) 223–230. [101] R.K. Sethi, M.J. Neavyn, H.E. Rubash, A.S. Shanbhag, Macrophage response to crosslinked and conventional UHMWPE, Biomaterials 24 (2003) 2561–2573. [102] A.S. Shanbhag, J.J. Jacobs, J. Black, J.O. Galante, T.T. Glant, Macrophage/particle interactions: effect of size, composition and surface area, J. Biomed. Mater. Res. 28 (1994) 81–90. [103] H.-W. Fang, Y.-C. Ho, C.-B. Yang, H.-L. Liu, F.-Y. Ho, Y.-C. Lu, et al. Preparation of UHMWPE particles and establishment of inverted macrophage cell model to investigate wear particles induced bioactivites, J. Biochem. Biophys. Methods 68 (2006) 175–187. [104] D.W. Howie, B. Vernon-Roberts, R. Oakeshott, B. Manthey, A rat model of resorption of bone at the cement-bone interface in the presence of polyethylene wear particles, J. Bone Joint Surg. Am. 70 (1988) 257–263. [105] G. Pap, A. Machner, T. Rinnert, D. Horler, R.E. Gay, H. Schwarzberg, et al. Development

[106]

[107]

[108]

[109]

[110]

[111]

[112]

[113]

[114]

[115]

525

and characteristics of a synovial-like interface membrane around cemented tibial hemiarthroplasties in a novel rat model of aseptic prosthesis loosening, Arthritis Rheum. 44 (2001) 956–963. A.S. Shanbhag, C.T. Hasselman, H.E. Rubash, The John Charnley Award. Inhibition of wear debris mediated osteolysis in a canine total hip arthroplasty model, Clin. Orthop. (344) (1997) 33–43. S.B. Goodman, V.L. Fornasier, J. Lee, J. Kei, The histological effects of the implantation of different sizes of polyethylene particles in the rabbit tibia, J. Biomed. Mater. Res. 24 (1990) 517–524. S.G. Kaar, A.A. Ragab, S.J. Kaye, B.A. Kilic, T. Jinno, V.M. Goldberg, et al. Rapid repair of titanium particle-induced osteolysis is dramatically reduced in aged mice, J. Orthop. Res. 19 (2001) 171–178. K.D. Merkel, J.M. Erdmann, K.P. McHugh, Y. Abu-Amer, F.P. Ross, S.L. Teitelbaum, Tumor necrosis factor-alpha mediates orthopedic implant osteolysis, Am. J. Pathol. 154 (1999) 203–210. E.M. Schwarz, E.B. Benz, A.P. Lu, J.J. Goater, A.V. Mollano, R.N. Rosier, et al. Quantitative small-animal surrogate to evaluate drug efficacy in preventing wear debris-induced osteolysis, J. Orthop. Res. 18 (2000) 849–855. P.H. Wooley, R. Morren, J. Andary, S. Sud, S.-Y. Yang, L. Mayton, et al. Inflammatory responses to orthopaedic biomaterials in the murine air pouch, Biomaterials 23 (2002) 517–526. S. Yang, W. Ren, Y. Park, A. Sieving, S. Hsu, S. Nasser, et al. Diverse cellular and apoptotic responses to variant shapes of UHMWPE particles in a murine model of inflammation, Biomaterials 23 (2002) 3535–3543. W. Ren, S.Y. Yang, H.W. Fang, S. Hsu, P.H. Wooley, Distinct gene expression of receptor activator of nuclear factor-kappaB and rank ligand in the inflammatory response to variant morphologies of UHMWPE particles, Biomaterials 24 (2003) 4819–4826. W.P. Ren, D.C. Markel, R. Zhang, X. Peng, B. Wu, H. Monica, et al. Association between UHMWPE particle-induced inflammatory osteoclastogenesis and expression of RANKL, VEGF, and Flt-1 in vivo, Biomaterials 27 (2006) 5161–5169. K.J. Kim, Y. Kobayashi, T. Itoh, Osteolysis model with continuous infusion of polyethylene particles, Clin. Orthop. (352) (1998) 46–52.

526

[116] P.G. Ren, A. Irani, Z. Huang, T. Ma, S. Biswal, S.B. Goodman, Continuous infusion of UHMWPE particles induces increased bone macrophages and osteolysis, Clin. Orthop. Relat. Res. 469 (2011) 113–122. [117] T. Ma, Z. Huang, P.G. Ren, R. McCally, D. Lindsey, R.L. Smith, et al. An in vivo murine model of continuous intramedullary infusion of polyethylene particles, Biomaterials 29 (2008) 3738–3742. [118] L.M. Childs, J.J. Goater, R.J. O’Keefe, E.M. Schwarz, Effect of anti-tumor necrosis factoralpha gene therapy on wear debris-induced osteolysis, J. Bone Joint Surg. Am. 83-A (2001) 1789–1797. [119] G.-I. Im, B.-C. Kwon, K.-B. Lee, The effect of COX-2 inhibitors on periprosthetic osteolysis. [see comment], Biomaterials 25 (2004) 269–275. [120] C. Wedemeyer, C. Neuerburg, A. Pfeiffer, A. Heckelei, F. von Knoch, G. Hilken, et al. Polyethylene particle-induced bone resorption in substance P-deficient mice, Calcif. Tissue Int. 80 (2007) 268–274. [121] E.M. Greenfield, J.M. Tatro, M.V. Smith, E.A. Schnaser, D. Wu, PI3Kgamma deletion reduces variability in the in vivo osteolytic response induced by orthopaedic wear particles, J. Orthop. Res. 29 (2011) 1649–1653. [122] E.E. Carmody, E.M. Schwarz, J.E. Puzas, R.N. Rosier, R.J. O’Keefe, Viral interleukin-10 gene inhibition of inflammation, osteoclastogenesis, and bone resorption in response to titanium particles, Arthritis Rheum. 46 (2002) 1298–1308. [123] S. Yang, B. Wu, L. Mayton, C.H. Evans, P.D. Robbins, P.H. Wooley, IL-1Ra and vIL-10 gene transfer using retroviral vectors ameliorates particle-associated inflammation in the murine air pouch model, Inflamm. Res. 51 (2002) 342–350. [124] W. Ren, R. Zhang, D.C. Markel, B. Wu, X. Peng, M. Hawkins, et al. Blockade of vascular endothelial growth factor activity suppresses wear debris-induced inflammatory osteolysis, J. Rheumatol. 34 (2007) 27–35. [125] W. Ren, B. Wu, X. Peng, L. Mayton, D. Yu, J. Ren, et al. Erythromycin inhibits wear debrisinduced inflammatory osteolysis in a murine model, J. Orthop. Res. 24 (2006) 280–290. [126] F. von Knoch, A. Heckelei, C. Wedemeyer, G. Saxler, G. Hilken, J. Brankamp, et al. Suppression of polyethylene particle-in-

UHMWPE Biomaterials Handbook

[127]

[128]

[129]

[130]

[131]

[132]

[133]

[134]

[135]

[136]

duced osteolysis by exogenous osteoprotegerin, J. Biomed. Mater. Res. A 75 (2005) 288–294. M. von Knoch, C. Wedemeyer, A. Pingsmann, F. von Knoch, G. Hilken, C. Sprecher, et al. The decrease of particle-induced osteolysis after a single dose of bisphosphonate, Biomaterials 26 (2005) 1803–1808. W. Ren, B. Wu, X. Peng, J. Hua, H.-N. Hao, P.H. Wooley, Implant wear induces inflammation, but not osteoclastic bone resorption, in RANK(–/–) mice, J. Orthop. Res. 24 (2006) 1575–1586. S.-Y. Yang, L. Mayton, B. Wu, J.J. Goater, E.M. Schwarz, P.H. Wooley, Adeno-associated virus-mediated osteoprotegerin gene transfer protects against particulate polyethylene-induced osteolysis in a murine model, Arthritis Rheum. 46 (2002) 2514–2523. S.B. Goodman, E. Gibon, J. Pajarinen, T.H. Lin, M. Keeney, P.G. Ren, et al. Novel biological strategies for treatment of wear particleinduced periprosthetic osteolysis of orthopaedic implants for joint replacement, J. R. Soc. Interface 11 (2014) 20130962. S. Wei, H. Kitaura, P. Zhou, F.P. Ross, S.L. Teitelbaum, IL-1 mediates TNF-induced osteoclastogenesis, J. Clin. Invest. 115 (2005) 282–290. E. Gibon, T. Ma, P.G. Ren, K. Fritton, S. Biswal, Z. Yao, et al. Selective inhibition of the MCP-1-CCR2 ligand-receptor axis decreases systemic trafficking of macrophages in the presence of UHMWPE particles, J. Orthop. Res. 30 (2012) 547–553. H. Wang, T.H. Jia, N. Zacharias, W. Gong, H.X. Du, P.H. Wooley, et al. Combination gene therapy targeting on interleukin-1beta and RANKL for wear debris-induced aseptic loosening, Gene Ther. 20 (2013) 128–135. A.S. Shanbhag, A.M. Kaufman, K. Hayata, H.E. Rubash, Assessing osteolysis with use of high-throughput protein chips, J. Bone Joint Surg. Am. 89 (2007) 1081–1089. J. Gallo, J. Vaculova, S.B. Goodman, Y.T. Konttinen, J.P. Thyssen, Contributions of human tissue analysis to understanding the mechanisms of loosening and osteolysis in total hip replacement, Acta Biomater. 10 (2014) 2354–2366. I. Bos, D. Fredebold, J. Diebold, U. Lohrs, Tissue reactions to cemented hip sockets. Histologic and morphometric autopsy study

28:  Pathophysiologic Reactions to UHMWPE Wear Particles

[137]

[138]

[139] [140]

[141]

[142]

[143]

[144]

[145]

[146] [147]

[148]

of 25 acetabula, Acta Orthop. Scand. 66 (1995) 1–8. V. Fornasier, J. Wright, J. Seligman, The histomorphologic and morphometric study of asymptomatic hip arthroplasty. A postmortem study, Clin. Orthop. Relat. Res. (1991) 272– 282. T.P. Schmalzried, L.M. Kwong, M. Jasty, R.C. Sedlacek, T.C. Haire, D.O. O’Connor, et al. The mechanism of loosening of cemented acetabular components in total hip arthroplasty. Analysis of specimens retrieved at autopsy, Clin. Orthop. (1992) 60–78. F.S. Kaplan, D.L. Glaser, N. Hebela, E.M. Shore, Heterotopic ossification, J. Am. Acad Orthop. Surg. 12 (2004) 116–125. K. Liu, S. Tripp, L.J. Layfield, Heterotopic ossification: review of histologic findings and tissue distribution in a 10-year experience, Pathol. Res. Pract. 203 (2007) 633–640. L. Rifas, T-cell cytokine induction of BMP-2 regulates human mesenchymal stromal cell differentiation and mineralization, J. Cell Biochem. 98 (2006) 706–714. D.R.S. Steiner, N.C. Gonzalez, J.G. Wood, Mast cells mediate the microvascular inflammatory response to systemic hypoxia, J. Appl. Physiol. 94 (2003) 325–334. T.A. Freeman, J. Parvizi, C.J. Dela Valle, M.J. Steinbeck, Mast cells and hypoxia drive tissue metaplasia and heterotopic ossification in idiopathic arthrofibrosis after total knee arthroplasty, Fibrogenesis Tissue Repair 3 (2010) 17. P. Koulouvaris, K. Ly, L.B. Ivashkiv, M.P. Bostrom, B.J. Nestor, T.P. Sculco, et al. Expression profiling reveals alternative macrophage activation and impaired osteogenesis in periprosthetic osteolysis, J. Orthop. Res. 26 (2008) 106–116. R.J. Looney, E.M. Schwarz, A. Boyd, R.J. O’Keefe, Periprosthetic osteolysis: an immunologist’s update, Curr. Opin. Rheumatol. 18 (2006) 80–87. E. Ingham, J. Fisher, The role of macrophages in osteolysis of total joint replacement, Biomaterials 26 (2005) 1271–1286. W.J. Maloney, R.L. Smith, Periprosthetic osteolysis in total hip arthroplasty: the role of particulate wear debris, Instr. Course Lect. 45 (1996) 171–182. S.L. Teitelbaum, Osteoclasts; culprits in inflammatory osteolysis, Arthritis Res. Ther. 8 (2006) 201.

527

[149] P.H. Wooley, E.M. Schwarz, Aseptic loosening, Gene Ther. 11 (2004) 402–407. [150] A. Kobayashi, M.A. Freeman, W. Bonfield, Y. Kadoya, T. Yamac, N. Al-Saffar, et al. Number of polyethylene particles and osteolysis in total joint replacements. A quantitative study using a tissue-digestion method, J. Bone Joint Surg. Br. 79 (1997) 844–848. [151] Y. Kadoya, P.A. Revell, A. Kobayashi, N. alSaffar, G. Scott, M.A. Freeman, Wear particulate species and bone loss in failed total joint arthroplasties, Clin. Orthop. Relat. Res. (1997) 118–129. [152] Y. Kadoya, A. Kobayashi, H. Ohashi, Wear and osteolysis in total joint replacements. [see comment], Acta Orthop. Scand. Suppl. 278 (1998) 1–16. [153] J. Gallo, S.B. Goodman, Y.T. Konttinen, M.A. Wimmer, M. Holinka, Osteolysis around total knee arthroplasty: a review of pathogenetic mechanisms, Acta Biomater. 9 (2013) 8046– 8058. [154] D. Nam, M.P. Bostrom, A. Fahlgren, Emerging ideas: instability-induced periprosthetic osteolysis is not dependent on the fibrous tissue interface, Clin. Orthop. Relat. Res. 471 (2013) 1758–1762. [155] H. Alidousti, M. Taylor, N.W. Bressloff, Do capsular pressure and implant motion interact to cause high pressure in the periprosthetic bone in total hip replacement?, J. Biomech. Eng. 133 (2011) 121001. [156] T.P. Schmalzried, K.H. Akizuki, A.N. Fedenko, J. Mirra, The role of access of joint fluid to bone in periarticular osteolysis. A report of four cases, J. Bone Joint Surg. Am. 79 (1997) 447–452. [157] M.T. Manley, J.A. D’Antonio, W.N. Capello, A.A. Edidin, Osteolysis: a disease of access to fixation interfaces, Clin. Orthop. Relat. Res. (2002) 129–137. [158] E.M. Greenfield, Y. Bi, A.A. Ragab, V.M. Goldberg, R.R. Van De Motter, The role of osteoclast differentiation in aseptic loosening, J. Orthop. Res. 20 (2002) 1–8. [159] A. Sabokbar, Y. Fujikawa, S. Neale, D.W. Murray, N.A. Athanasou, Human arthroplasty derived macrophages differentiate into osteoclastic bone resorbing cells, Ann. Rheum. Dis. 56 (1997) 414–420. [160] D.R. Haynes, T.N. Crotti, A.E. Potter, M. Loric, G.J. Atkins, D.W. Howie, et al. The osteoclastogenic molecules RANKL and RANK

528

[161]

[162]

[163]

[164]

[165] [166]

[167]

[168]

[169]

[170]

UHMWPE Biomaterials Handbook

are associated with periprosthetic osteolysis, J. Bone Joint Surg. Br. 83 (2001) 902–911. A. Sabokbar, O. Kudo, N.A. Athanasou, Two distinct cellular mechanisms of osteoclast formation and bone resorption in periprosthetic osteolysis, J. Orthop. Res. 21 (2003) 73–80. J.W. Xu, Y.T. Konttinen, V. Waris, H. Patiala, T. Sorsa, S. Santavirta, Macrophage-colony stimulating factor (M-CSF) is increased in the synovial-like membrane of the periprosthetic tissues in the aseptic loosening of total hip replacement (THR), Clin. Rheumatol. 16 (1997) 243–248. T. Gehrke, C. Sers, L. Morawietz, G. Fernahl, J. Neidel, L. Frommelt, et al. Receptor activator of nuclear factor kappaB ligand is expressed in resident and inflammatory cells in aseptic and septic prosthesis loosening, Scand. J. Rheumatol. 32 (2003) 287–294. T.N. Crotti, M.D. Smith, D.M. Findlay, H. Zreiqat, M.J. Ahern, H. Weedon, et al. Factors regulating osteoclast formation in human tissues adjacent to peri-implant bone loss: expression of receptor activator NFkappaB, RANK ligand and osteoprotegerin, Biomaterials 25 (2004) 565–573. W.J. Boyle, W.S. Simonet, D.L. Lacey, Osteoclast differentiation and activation, Nature 423 (2003) 337–342. T. Suda, K. Kobayashi, E. Jimi, N. Udagawa, N. Takahashi, The molecular basis of osteoclast differentiation and activation, Novartis Found. Symp. 232 (2001) 235–247 discussion 47–50. M.J. Steinbeck, W.H. Appel Jr., A.J. Verhoeven, M.J. Karnovsky, NADPH-oxidase expression and in situ production of superoxide by osteoclasts actively resorbing bone, J. Cell Biol. 126 (1994) 765–772. M.J. Steinbeck, J.K. Kim, M.J. Trudeau, P.V. Hauschka, M.J. Karnovsky, Involvement of hydrogen peroxide in the differentiation of clonal HD-11EM cells into osteoclast-like cells, J. Cell Physiol. 176 (1998) 574–587. S. Landgraeber, F. Loer, H. Heep, T. Classen, F. Grabellus, M. Totsch, et al. Tartrateresistant acid phosphatase 5b and C-terminal telopeptides of type I collagen as markers for diagnosis of aseptic loosening after total hip replacement, Arch. Orthop. Trauma. Surg. 130 (2010) 441–445. D. Granchi, A. Pellacani, M. Spina, E. Cenni, L.M. Savarino, N. Baldini, et al. Serum lev-

[171]

[172] [173]

[174]

[175]

[176]

[177]

[178]

[179] [180]

[181]

els of osteoprotegerin and receptor activator of nuclear factor-kappaB ligand as markers of periprosthetic osteolysis, J. Bone Joint Surg. Am. 88 (2006) 1501–1509. T. von Schewelov, A. Carlsson, L. Dahlberg, Cross-linked N-telopeptide of type I collagen (NTx) in urine as a predictor of periprosthetic osteolysis, J. Orthop. Res. 24 (2006) 1342–1348. W.H. Harris, Osteolysis and particle disease in hip replacement. A review, Acta Orthop. Scand. 65 (1994) 113–123. A. Del Buono, V. Denaro, N. Maffulli, Genetic susceptibility to aseptic loosening following total hip arthroplasty: a systematic review, Br. Med. Bull. 101 (2012) 39–55. R.D. Devlin, S.V. Reddy, R. Savino, G. Ciliberto, G.D. Roodman, IL-6 mediates the effects of IL-1 or TNF, but not PTHrP or 1,25(OH)2D3, on osteoclast-like cell formation in normal human bone marrow cultures, J. Bone Miner. Res. 13 (1998) 393–399. S.C. Manolagas, R.L. Jilka, Bone marrow, cytokines, and bone remodeling. Emerging insights into the pathophysiology of osteoporosis, N. Engl. J. Med. 332 (1995) 305–311. E.A. Phillips, G.R. Klein, H.E. Cates, S.M. Kurtz, M.J. Steinbeck, Histological characterization of periprosthetic tissue responses for metal-on-metal hip replacement, J. Long Term Eff. Med. Implants 24 (2014) 13–23. G. Grammatopoulos, H. Pandit, A. Kamali, F. Maggiani, S. Glyn-Jones, H.S. Gill, et al. The correlation of wear with histological features after failed hip resurfacing arthroplasty, J. Bone Joint Surg. Am. 95 (2013) e81. P. Campbell, E. Ebramzadeh, S. Nelson, K. Takamura, K. De Smet, H.C. Amstutz, Histological features of pseudotumor-like tissues from metal-on-metal hips, Clin. Orthop. Relat. Res. 468 (2010) 2321–2327. C.J. Della Valle, J.D. Zuckerman, P.E. Di Cesare, Periprosthetic sepsis, Clin. Orthop. Relat. Res. (420) (2004) 26–31. J.H. Schroeder, L. Morawietz, G. Matziolis, D. Leutloff, T. Gehrke, V. Krenn, et al. Loosening of joint arthroplasty – the potential of the periprosthetic membrane, J. Bone Joint Surg. Br. 88-B (2006) 64. C.L. Jacovides, R. Kreft, B. Adeli, B. Hozack, G.D. Ehrlich, J. Parvizi, Successful identification of pathogens by polymerase chain reaction (PCR)-based electron spray ionization time-of-flight mass spectrometry (ESI-TOF-

28:  Pathophysiologic Reactions to UHMWPE Wear Particles

[182]

[183]

[184]

[185]

[186]

[187]

[188]

[189]

[190]

[191]

MS) in culture-negative periprosthetic joint infection, J. Bone Joint Surg. Am. 94 (2012) 2247–2254. G.M. Robbins, B.A. Masri, D.S. Garbuz, C.P. Duncan, Evaluation of pain in patients with apparently solidly fixed total hip arthroplasty components, J. Am. Acad. Orthop. Surg. 10 (2002) 86–94. S. Cazzavillan, R. Ratanarat, C. Segala, V. Corradi, M. de Cal, D. Cruz, et al. Inflammation and subclinical infection in chronic kidney disease: a molecular approach, Blood Purif. 25 (2007) 69–76. A. Pajkos, A.K. Deva, K. Vickery, C. Cope, L. Chang, Y.E. Cossart, Detection of subclinical infection in significant breast implant capsules. [see comment], Plast. Reconstr. Surg. 111 (2003) 1605–1611. L. Savarino, N. Baldini, C. Tarabusi, A. Pellacani, A. Giunti, Diagnosis of infection after total hip replacement, J. Biomed. Mater. Res. A. 70 (2004) 139–145. C. Deirmengian, K. Kardos, P. Kilmartin, A. Cameron, K. Schiller, R.E. Booth Jr., et al. The Alpha-defensin test for periprosthetic joint infection outperforms the leukocyte esterase test strip, Clin. Orthop. Relat. Res. 473 (1) (2015) 198–203. C. Deirmengian, K. Kardos, P. Kilmartin, A. Cameron, K. Schiller, J. Parvizi, Combined measurement of synovial fluid alpha-Defensin and C-reactive protein levels: highly accurate for diagnosing periprosthetic joint infection, J. Bone Joint Surg. Am. 96 (2014) 1439–1445. C. Deirmengian, K. Kardos, P. Kilmartin, A. Cameron, K. Schiller, J. Parvizi, Diagnosing periprosthetic joint infection: has the era of the biomarker arrived?, Clin Orthop Relat Res 472 (2014) 3254–3262. V. Krenn, L. Morawietz, G. Perino, H. Kienapfel, R. Ascherl, G.J. Hassenpflug, et al. Revised histopathological consensus classification of joint implant related pathology, Pathol. Res. Pract. 210 (2014) 779–786. V. Krenn, J.P. Kretzer, P. Thomas, M. Thomsen, S. Usbeck, L. Scheuber, et al. Update on endoprosthesis pathology: particle algorithm for particle identification in the SLIM, Sem. Arthroplasty 24 (2013) 265–275. J. Gallo, M. Holinka, C.S. Moucha, Antibacterial surface treatment for orthopaedic implants, Int. J. Mol. Sci. 15 (2014) 13849–13880.

529

[192] D.J. Moojen, G. van Hellemondt, H.C. Vogely, B.J. Burger, G.H. Walenkamp, N.J. Tulp, et al. Incidence of low-grade infection in aseptic loosening of total hip arthroplasty, Acta Orthop. 81 (2010) 667–673. [193] J.L. Nalepka, M.J. Lee, M.J. Kraay, R.E. Marcus, V.M. Goldberg, X. Chen, et al. Lipopolysaccharide found in aseptic loosening of patients with inflammatory arthritis, Clin. Orthop. Relat. Res. 451 (2006) 229–235. [194] C.H. Geerdink, B. Grimm, R. Ramakrishnan, J. Rondhuis, A.J. Verburg, A.J. Tonino, Crosslinked polyethylene compared to conventional polyethylene in total hip replacement: preclinical evaluation, in-vitro testing and prospective clinical follow-up study, Acta Orthop. 77 (2006) 719–725. [195] Y. Bi, T.O. Collier, V.M. Goldberg, J.M. Anderson, E.M. Greenfield, Adherent endotoxin mediates biological responses of titanium particles without stimulating their phagocytosis, J. Orthop. Res. 20 (2002) 696–703. [196] Y. Bi, J.M. Seabold, S.G. Kaar, A.A. Ragab, V.M. Goldberg, J.M. Anderson, et al. Adherent endotoxin on orthopedic wear particles stimulates cytokine production and osteoclast differentiation, J. Bone Miner. Res. 16 (2001) 2082–2091. [197] E.M. Greenfield, Y. Bi, A.A. Ragab, V.M. Goldberg, J.L. Nalepka, J.M. Seabold, Does endotoxin contribute to aseptic loosening of orthopedic implants?, J. Biomed. Mater. Res. A 72 (2005) 179–185. [198] E.M. Greenfield, M.A. Beidelschies, J.M. Tatro, V.M. Goldberg, A.G. Hise, Bacterial pathogen-associated molecular patterns stimulate biological activity of orthopaedic wear particles by activating cognate Toll-like receptors, J. Biol. Chem. 285 (2010) 32378–32384. [199] A.U. Daniels, F.H. Barnes, S.J. Charlebois, R.A. Smith, Macrophage cytokine response to particles and lipopolysaccharide in vitro, J. Biomed. Mater. Res. 49 (2000) 469–478. [200] R.A. Smith, N.J. Hallab, In vitro macrophage response to polyethylene and polycarbonateurethane particles, J. Biomed. Mater. Res. A 93 (2010) 347–355. [201] C.A. Engh Jr., R.H. Hopper Jr., C. Huynh, H. Ho, S. Sritulanondha, C.A. Engh Sr., A prospective, randomized study of cross-linked and non-cross-linked polyethylene for total hip arthroplasty at 10-year follow-up, J. Arthroplasty 27 (2012) 2e1–7e1.

530

[202] S.M. Kurtz, H.A. Gawel, J.D. Patel, History and systematic review of wear and osteolysis outcomes for first-generation highly crosslinked polyethylene, Clin. Orthop. Relat. Res. 469 (2011) 2262–2277. [203] G.E. Thomas, D.J. Simpson, S. Mehmood, A. Taylor, P. McLardy-Smith, H.S. Gill, et al. The seven-year wear of highly cross-linked polyethylene in total hip arthroplasty: a doubleblind, randomized controlled trial using radiostereometric analysis, J. Bone Joint Surg. Am. 93 (2011) 716–722. [204] D.T. Schroder, N.H. Kelly, T.M. Wright, M.L. Parks, Retrieved highly crosslinked UHMWPE acetabular liners have similar wear damage as conventional UHMWPE, Clin. Orthop. Relat. Res. 469 (2011) 387–394. [205] S.B. Leung, H. Egawa, A. Stepniewski, S. Beykirch, C.A. Engh Jr., C.A. Engh Sr., Incidence and volume of pelvic osteolysis at early follow-up with highly cross-linked and noncross-linked polyethylene, J. Arthroplasty 22 (2007) 134–139. [206] N.A. Mall, R.M. Nunley, J.J. Zhu, W.J. Maloney, R.L. Barrack, J.C. Clohisy, The incidence of acetabular osteolysis in young patients with conventional versus highly crosslinked polyethylene, Clin. Orthop. Relat. Res. 469 (2011) 372–381. [207] R.L. Illgen II, L.M. Bauer, B.T. Hotujec, S.E. Kolpin, A. Bakhtiar, T.M. Forsythe, Highly crosslinked vs conventional polyethylene particles: relative in vivo inflammatory response, J. Arthroplasty 24 (2009) 117–124. [208] S. Utzschneider, V. Lorber, M. Dedic, A.C. Paulus, C. Schroder, O. Gottschalk, et al. Biological activity and migration of wear particles in the knee joint: an in vivo comparison of six different polyethylene materials, J. Mater. Sci. Mater. Med. 25 (2014) 1599–1612. [209] T.W. Bauer, P.A. Campbell, G. Hallerberg, How have new bearing surfaces altered the local biological reactions to byproducts of wear and modularity?, Clin. Orthop. Relat. Res. 472 (12) (2014) 3687–3698. [210] P.H. Wooley, How has the introduction of new bearing surfaces altered the biological ­reactions to byproducts of wear and modularity?, Clin. Orthop. Relat. Res. 472 (12) (2014) 3699–3708. [211] D.W. Howie, S.D. Neale, D.R. Haynes, O.T. Holubowycz, M.A. McGee, L.B. Solomon, et al. Periprosthetic osteolysis after total hip

UHMWPE Biomaterials Handbook

[212]

[213] [214]

[215]

[216]

[217]

[218]

[219]

[220]

[221]

replacement: molecular pathology and clinical management, Inflammopharmacology 21 (2013) 389–396. R.M. Baxter, A. Ianuzzi, T.A. Freeman, S.M. Kurtz, M.J. Steinbeck, Distinct immunohistomorphologic changes in periprosthetic hip tissues from historical and highly crosslinked UHMWPE implant retrievals, J. Biomed. Mater. Res. A 95 (2010) 68–78. N. Athanasou, The pathology of joint replacement, Curr. Diag. Pathol. 8 (2002) 26–32. S. Ito, T. Matsumoto, H. Enomoto, H. Shindo, Histological analysis and biological effects of granulation tissue around loosened hip prostheses in the development of osteolysis, J. Orthop. Sci. 9 (2004) 478–487. K.J. Kim, J. Chiba, H.E. Rubash, In vivo and in vitro analysis of membranes from hip prostheses inserted without cement, J. Bone Joint Surg. Am. 76 (1994) 172–180. R.M. Baxter, T.A. Freeman, S.M. Kurtz, M.J. Steinbeck, Do tissues from THA revision of highly crosslinked UHMWPE liners contain wear debris and associated inflammation?, Clin. Orthop. Relat. Res. 469 (2011) 2308–2317. K. Knahr, M. Pospischill, P. Kottig, W. Schneider, H. Plenk Jr., Retrieval analyses of highly cross-linked polyethylene acetabular liners four and five years after implantation, J. Bone Joint Surg. Br. 89 (2007) 1036–1041. R.M. Baxter, D.W. MacDonald, S.M. Kurtz, M.J. Steinbeck, Characteristics of highly cross-linked polyethylene wear debris in vivo, J. Biomed. Mater. Res. A 101 (2013) 467–475. Y. Minoda, A. Kobayashi, A. Sakawa, M. Aihara, K. Tada, Sugama R., et al. Wear particle analysis of highly crosslinked polyethylene isolated from a failed total hip arthroplasty, J Biomed Mater Res A 86B (2008) 501–505. M. Endo, J.L. Tipper, D.C. Barton, M.H. Stone, E. Ingham, J. Fisher, Comparison of wear, wear debris and functional biological activity of moderately crosslinked and noncrosslinked polyethylenes in hip prostheses. Proceedings of the Institution of Mechanical Engineers Part H, Journal of engineering in medicine 216 (2002) 111–122. J.H. Ingram, M. Stone, J. Fisher, E. Ingham, The influence of molecular weight, crosslinking and counterface roughness on TNF-alpha production by macrophages in response to ultra high molecular weight polyethylene particles, Biomaterials 25 (2004) 3511–3522.