Pathophysiologic Reactions to UHMWPE Wear Particles

Chapter 23

Pathophysiologic Reactions to UHMWPE Wear Particles Marla J. Steinbeck, PhD, Ryan M. Baxter, PhD Candidate, and Theresa A. Freeman, PhD

23.1 Introduction 23.2 Rationale for Evaluating Tissue Responses 23.3 Immune System 23.3.1 Adaptive Immune Response 23.3.2 Cytokines and Chemokines 23.4 Immunologic Responses to Joint Replacement UHMWPE Wear Debris

23.5 In Vitro and In Vivo Models Used to Study the Immune Response to UHMWPE Wear Debris 23.6 Inflammatory- and Noninflammatory-Based Histomorphologic Changes in Periprosthetic Tissues 23.7 Current Considerations Based on More Recent Findings and Approaches to Tissue Analysis

23.1  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 and the associated adverse biologic reaction elicited by wear debris [1] (Chapter 27). The most obvious gross, clinical manifestation associated with wear debris generation is bone loss (osteolysis; Figure 23.1), which has been identified as a major reason for implant loosening and the need for revision surgery after total hip replacement [2–3]. In 1977, a seminal paper by Hans-Georg Willert demonstrated macrophage activation by UHMWPE wear debris generated by movement of the articulating implant surfaces and by the movement of the implant against surrounding bone [4]. These initial observations led to numerous studies characterizing the chronic inflammatory response in periprosthetic tissue. The challenge in assessing the pathophysiologic response to wear debris associated with joint replacement surgery is to accurately UHMWPE Biomaterials Handbook Copyright © 2009, 2009 Academic Press. Inc. All rights of reproduction in any form reserved.

23.8

Exacerbation of the Immune Response to Wear Debris as a Result of Subclinical Infection 23.9 Comparative Pathophysiologic Changes in Periprosthetic Hip Tissues from Historical and Highly Crosslinked UHMWPE Implant Retrievals 23.10 Conclusion 23.11 Acknowledgments References

characterize wear particle generation and the ensuing tissue response. This requires complex cellular and molecular analysis of periprosthetic tissues at both early and late implantation times. The distribution of wear debris is another confounding factor because the cyclic loading of an articulating joint implant may result in intermittent waves of joint fluid pressure. This may distribute wear particles both locally and to more remote sites along the implant interface, as well as other organs. Locally, the dissemination of particles is limited by the density of the surrounding tissue. Large particles are trapped in dense, collagen-rich joint connective tissue, while smaller particles are able to move more freely. A recent cadaveric study showed UHMWPE wear debris was disseminated to the lymph nodes, spleen, and liver after joint replacement surgery [5]. Most disseminated particles were smaller than one micron, but particles as large as 50 microns were identified in abdominal lymph nodes. Lymphatic transport through perivascular lymph channels, as free or phagocytosed particles within macrophages, is the most probable route for wear debris distribution. The nature and ultimate fate of the wear debris, 341

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Figure 23.1  Radiograph with pronounced regions of acetabular and femoral lysis (radiolucency indicated with red arrows) from a historical, gamma-air sterilized UHMWPE hip replacement revised 11.4 years post-implantation.

and the implications of long-term systemic exposure, are among the least understood aspects of joint arthroplasty. This is not surprising because the difficulty of particle detection, coupled with the number of tissue locations required to analyze particle distribution, makes this an overwhelming task. 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 particles. Potential factors involved in individual-specific responses include genetic polymorphisms in matrix metalloproteinase 1, IL-6, TNF-, and the vitamin D receptor [6–8]. In general, the frequently undetectable progression of inflammatory, biochemical and morphological changes in tissues surrounding the implant impose a major challenge.

23.2  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 biomarkers) and treatment modalities to suppress these responses. Insights

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into the loss of total joint replacement function have been gained by analyzing the cellular and molecular changes in periprosthetic tissues. Cellular and molecular biological techniques, including histology, histochemistry, immunohistochemistry, in situ hybridization, polymerase chain reaction (PCR), and Western and Northern blot analysis, have yielded important information concerning the biologic processes in periprosthetic tissues [1, 9–10]. Although gains have been made in understanding the contribution of UHMWPE wear debris volume, size, shape, and biochemical or protein binding characteristics to the tissue response, improvements in methods to achieve a complete understanding of the local and systemic pathophysiologic responses are needed. Improved methods of tissue analysis will aid in developing a standardized approach to evaluate the effects of wear particles for each new type of implant. This information is needed to make improvements in implant design, ultimately resulting in better implant longevity. For those patients with existing implants, this information, as previously mentioned, will aid in the development of diagnostic tests and treatment modalities to reverse the existing host responses.

23.3  Immune system Since the seminal work by Hans-Georg Willert, which demonstrated macrophage activation by UHMWPE wear debris, interest in understanding the complete immune response in periprosthetic tissue has exploded [4]. For most nonimmunologists, this complex area is difficult to grasp, but hopefully the following information will provide a basis for a better understanding of the immune system. The cells that carry out the immune response are called white blood cells or leukocytes. Leukocytes are subdivided into two groups of cells. The first group is the granulocytes, which are cells that contain cytosolic granules and include neutrophils, eosinophils, and basophils. 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. 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 [11]. The second group is composed of monocytes and lymphocytes. Monocytic cells mature in the bone marrow, enter the bloodstream and, unlike the other leukocytes, are found in most tissues. After recruitment to the tissues, they are referred to as tissue macrophages, and depending on the specific tissue they may be referred to as histiocytes, dendritic cells (skin), microglial cells (brain), Kupffer cells (liver), etc. These cells make up part of the body’s first line of defense against infectious agents or other foreign material,

Chapter  |  23  Pathophysiologic Reactions to UHMWPE Wear Particles

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. Lymphocytes 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 release antibodies, while T cells form helper (TH) or cytotoxic (TC) T cells. Only lymphocytes can recognize and differentiate between specific foreign (nonself) and self- molecules (antigens). A separate population of T cells, called regulatory T cells (Treg) specializes in mediating immune suppression. Disruption in the function of these cells is the primary cause of chronic inflammatory and autoimmune diseases. The immune response is divided into innate immunity and adaptive immunity. The innate immune system is constitutively on guard, reacts immediately, and is responsible for the initial defense against infectious agents and other foreign particles. This response is not specific; therefore, it is not dependant on the type of foreign body or nonhost component. The innate immune system consists of physical (skin and mucosal membranes) and chemical (mucous and antimicrobial peptides) barriers, blood proteins (acute phase proteins and complement), cytokines, phagocytic cells (neutrophils and macrophages), and natural killer cells (NK). Neutrophils and macrophages perform various host defense functions that rely on phagocytic uptake of infectious agents and other foreign particles. Phagocytes are equipped with multiple antimicrobial mechanisms that become activated upon initial contact with foreign particles. NK cells undergo maturation in the bone marrow; most contain granules, but they resemble lymphocytes rather than granulocytes in their appearance. 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 not require prior host exposure to the target cells and is mediated by granule exocytosis.

23.3.1  Adaptive Immune Response 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 antigen specific, 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, 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

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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 role of NK cells in the adaptive immune response is to produce cytokines that modulate emerging T and B cell responses and eliminate infected or abnormal host cells prior to T and B cell activation.

23.3.2  Cytokines and Chemokines Cytokines are cellular proteins (chemical messenger proteins) that mediate inflammation and communication between cells of the immune system, but they can affect 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 interleukins (IL), which at the present time include IL-1 to IL-34 and interferons –. 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 or other foreign particles. 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, in response to specific stimuli.

23.4  Immunologic responses to joint replacement UHMWPE wear debris Following a large total joint arthroplasty, a newly formed joint capsule or pseudosynovial membrane is typically formed around the implant within the joint space [3]. During this time, capsular tissue becomes established, followed by the formation of an intermediate, highly vascularized fibrous membrane [4]. At the time of revision surgery for aseptic implant loosening, an extended and thickened fibrous membrane with increased numbers of histiocytes and focal areas of decreased vascularization is typically present [12]. The predominant cells found in the intermediate fibrous membrane and other periprosthetic tissues include fibroblasts, histiocytes, infiltrated peripheral blood monocytes, and multinucleated giant cells [10, 13–14] (Figure 23.2). Interspersed throughout the tissue are both micron (typically from gamma air-sterilized UHMWPE components) and submicron UHMWPE debris [15–17]. Most of the UHMWPE particles, ranging in size from 0.1–10 m (typically less than 2 m), are ingested and

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Bone resorption

Osteoclastogenesis

Giant cell Inflammatory stimuli: Acute-TNF, IL-1, IL-6 Chronic - RANKL, IL-8

PE

Monocytes / Macrophage

Osteoclast precursor cell

IL-17 Blood vessel

Synovial T cell (TH17 cell) Synovial fibroblasts

Synovial macrophages (Histiocyte)

Wear particles Figure 23.2  Diagram of inflammatory changes preceeding osteolysis. The infiltration of immune cells, including monocytes and T cells, and activation of resident synovial fibroblasts and histiocytes in response to UHMWPE wear debris leads to the production of chemokines, cytokines, and growth factors. Giant cells form in response to larger wear debris. Monocyte/macrophages differentiate into osteoclasts, which are the cells responsible for bone resorption.

(a) (b)tissue using polarized light microscopy. (A) Micron- and submicron-sized Figure 23.3  UHMWPE wear debris observed in situ in periprosthetic hip UHMWPE wear debris (birefringent particles) within phagocytic histiocytes; (B) large UHMWPE wear debris (approximately 300 m) in periprosthetic tissue from a historical, gamma-air sterilized UHMWPE hip replacement revised 15.6 years post-implantation. Scale interval represents 10 m in both images.

found within phagosomes of the histiocytes and macrophages (Figure 23.3). The fusion of macrophages to form giant cells occurs in an attempt to ingest the UHMWPE particles, usually 10 m [18], because 5 m particles have been observed within these multinucleated giant cells

(Figure 23.4) [19]. The actual or attempted ingestion of particles, referred to as phagocytosis or frustrated phagocytosis, respectively, occurs through nonspecific receptors on the cell surfaces and results in activation of these cells. Activation marks the beginning of a chronic inflammatory

Chapter  |  23  Pathophysiologic Reactions to UHMWPE Wear Particles

Figure 23.4  CD3 immunostained T cells (red arrows) and foreign body giant cell (green arrow) localized with UHMWPE wear debris (yellow arrows) from a historical, gamma-air sterilized UHMWPE hip replacement revised 14.2 years post-implantation. 200 magnification. Scale interval represents 10 m.

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 of the UHMWPE wear debris, the cells release protein degrading enzymes and destructive reactive oxygen and nitrogen species (RONS) [20–22]. Thus, without the ability to remove the initiating wear debris stimulus, the inflammatory response continues, and rather than achieving a resolution thereby returning the tissue to a normal functional state, further tissue damage occurs. 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 [23]. 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. Based on numerous studies of the periprosthetic tissues, it is the activation of both recruited and resident cells that leads to the production and release of cytokines, chemokines, and growth factors by these cells. The acute response proinflammatory cytokines and chemokines produced by activated fibroblasts, macrophages, and mast cells include IL-1, IL-1, IL-6, and TNF- [24–27]. In most inflammatory reactions, the acute phase is typically a short-lived response, followed by the proinflammatory cytokine and chemokine release that perpetuates a chronic inflammatory response, such as IL-6, IL-8, and monocyte chemoattractant protein (MCP-1), which are also detected

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in these tissues [6, 28–30]. However, given the continuous introduction of wear particles into the tissue, the acute inflammatory phase may be recurrent, at least during the early implantation years. While the focus has been on the innate immune response, low numbers of T cells have been observed in periprosthetic membrane tissue [27, 31–32]. The role of T cells is not clear. In a subset of patients, however, there may be a hypersensitivity immune response that is directed at an UHMWPE particle containing bound immunostimulatory proteins [33] or altered, host protein from damaged tissue [34]. A Type II antibody-mediated hypersensitivity reaction is mediated by TH cells, B cells (plasma cells), and effector cells, typically monocyte/macrophages. The tissue damage associated with this response is mediated by activated macrophages and the release of lysosomal granule contents and the production of RONS. Type IV hypersensitivity or delayed-type hypersensitivity reactions may occur in response to the binding of small proteins (haptens, 1000 daltons) or other host cell material to UHMWPE particles. However, this type of reaction has predominantly been observed when metal debris was present in the periprosthetic tissue (Figure 23.5). Type IV hypersensitivity reactions are mediated by TH1 cells, and the tissue damage associated with this immune reaction is mediated by TC cells. An interesting recent development has been the recognition of a new subset of T cells producing IL-17 [35–37]. IL17 is produced predominantly by memory T cells and acts synergistically with TNF- to activate synovial fibroblast-like cells. TH17 cells have a distinctive cytokine profile, which includes IL-17, TNF- and RANKL (receptor activator of nuclear-receptor factor NFB ligand). These factors affect neutrophil, monocyte/macrophage, and osteoclast mobilization, differentiation, and activation [36]. Osteoclast formation and bone resorption is discussed in Section 23.6. TH17 cells play a role in inflammatory reactions, particularly those involved in autoimmune (self-directed) diseases directed against altered host (self) proteins. These cells are found in the synovial membrane of patients with autoimmune rheumatoid arthritis (RA), and the expression of extracellular matrix proteins and integrin receptors by synovial lining cells are similar in both RA and in tissues from patients with aseptic loosening of THRs [38]. 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 investigated. Like the TH17 cells, NK cells secrete cytokines that regulate T and B cell responses, and they are involved in the development of autoimmune diseases. Finally, the disregulation of Treg cells may also affect the tissue response to wear debris by failure to suppress the activity of stimulated immune cells. The involvement of T cell subsets and NK cells in periprosthetic tissue inflammation associated with UHMWPE wear debris will require additional studies.

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(A)

(B)

Figure 23.5  Combination of metal (A, red arrow) and UHMWPE wear debris (B) in periprosthetic hip tissue revised 19 years post­implantation. Main image: 100 magnification. Scale interval represents 10 m.

23.5  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 (0.1– 10 m) results in monocyte/macrophage activation, measured as an increase in the production of IL-1, IL-6, and TNF- in culture [15, 39–40]. In addition to size-based responses, elevated numbers of particles have been found at all locations in the periprosthetic tissue where chronic 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 [39]. In studies by Green et al. [39], the volume of particles was related to the cell number at two different concentrations, 10 m3:1 or 100 m3:1. Particles in the 0.24  0.094 m size range caused the greatest amount of IL-1, IL-6, and prostaglandin (PG)E2 to be released when the ratio of particles to cells was 10 m3:1. At the higher ratio, the larger sized particles caused an increased release of proinflammatory cytokines. Particle composition also effected of the release of proinflammatory cytokines by cultured monocyte/macrophages [41–43]. Specific wear morphologies can also instigate and affect the biological response in periprosthetic tissue. To investigate the effect of particle shape, Fang et al. developed an inverted monocyte/macrophage cell culture system and generated wear particles of varying size and shape [44]. Their findings showed that spherical particles of the same volume were ingested to a greater extent by monocyte/macrophages in culture than the elongated particles. Thus, in vitro

studies have shown that the biological response of monocyte/macrophages to UHMWPE wear debris is mediated by a variety of specific particle characteristics, including size, number, and shape. Because the pathophysiologic response to wear debris is not limited to the effects on monocyte/macrophages alone, animal models have been developed to study the in vivo response to wear debris. These animal models include rat [45–46], canine [47], and mouse [48–51] models. Particles within the 0.1–10 m size range isolated from periprosthetic tissues induced a local inflammatory response, which was increased as the particle numbers increased. Interestingly, Yang et al. [52] 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- and IL-1 production, relative to globular particles with similar surface area [53]. This result is interesting because in vitro cell studies showed that the globular particles were preferentially ingested by monocyte/macrophages in culture [44]. Mouse models have also been used to evaluate potential treatments for inflammation and subsequent osteolysis [50, 54–59]. The anti-inflammatory treatments tested include TNF- antagonists and a cyclooxygenase 2 inhibitor (PGE2 source). Treatment targeting osteoclasts and bone resorption include the RANKL receptor inhibitor osteoprotegerin (OPG) and bisphosphonates [29, 58, 60]. Numerous other potential targets have been identified and tested; most of these, however, have not been tested in the patient population because of potential side effects. For both the in vitro and in vivo animal studies, acute rather than chronic inflammatory cytokines were elevated in response to particle addition or injection, respectively. The drawback of these 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 and continuous particle generation [29].

Chapter  |  23  Pathophysiologic Reactions to UHMWPE Wear Particles

(A)

(B)

(C)

(D)

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Figure 23.6  Histomorphologic changes in periprosthetic hip tissue in response to UHMWPE wear debris. (A) CD68 antibody stain showing histiocytes (red arrows), 11 years post-implantation (YPIS). Main image: 200 magnification; (B) Foreign body giant cell (red arrow) with internalized UHMWPE wear debris, 15.4 YPIS. Main image: 100 magnification. Left inset of image B shows enlarged giant cell, and right inset shows UHMWPE wear debris that is exhibiting birefringence under polarized light. (C) Representative regions of fibrocartilage transition (red arrow) and tissue calcification (green arrows), 15.6 YPIS. Main image: 100 magnification; (D) Tissue necrosis with a few remaining intact cell nuclei, 19.7 YPIS. Both insets enlarged by 200% relative to original image. Scale interval represents 10 m.

23.6  Inflammatory- and noninflammatory-based histomorphologic changes in periprosthetic tissues 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, and last, but certainly not least, osteolysis of the surrounding bone (Figure 23.6). 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 [61]. Although these were cemented hip implants, and there was a contribution of both 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 the cement wear debris. This process did not plateau; it continued with increasing implant duration and the generation of UHMWPE wear debris. The histiocytes contained large amounts of phagocytosed wear debris and showed degenerative changes in chromatin structure and the disintegration of cell borders. In addition, giant cells were typically found around UHMWPE particles 30 m. 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. 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 [62–64].

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Inflammation, tissue damage, and decreased vascularization [12] can also instigate the conversion of fibrotic tissue to fibrocartilage and heterotopic ossification (bone formation in soft tissue). In addition to inflammation and inflammatory related tissue responses, the formation of fibrocartilage may have a more physical basis, related to micromotion of the implant [13]. 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, resulting in tissue necrosis or fibrocartilage formation [13]. 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 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 [65–68]. 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 [3, 6, 28]. 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., monocyte/macrophages and histiocytes) [3]. Evaluation of clinical data showed that patients revised for osteolysis consistently had UHMWPE particle quantities in the order of 10 billion particles per gram weight of tissue, suggesting the existence of a threshold for the infiltration and activation of monocyte/ macrophages and the onset of osteolysis [69, 70]. 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) [71, 72] (Chapter 27). Both micron and submicron (0.1–10 m) debris have been implicated as important contributors to the inflammatory response in periprosthetic tissue and the onset of osteolysis [15–17]. Particle-induced osteolysis, or loss of bone around the implant, can lead to implant loosening, which is the result of a tissue mediated loss of fixation (boneimplant ingrowth). In addition, loosening may occur due to inadequate initial fixation or mechanical loss of fixation over time. As a result, mechanically loose prostheses undergo excessive displacement, subsidence, and/or migration with the application of physiologic loads. Monocyte/macrophages in periprosthetic tissue have the potential to differentiate into fully functional osteoclasts, capable of bone resorption [73–75]. Soluble products

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released by activated macrophages and fibroblasts in the periprosthetic tissue control the activity, proliferation, and differentiation of osteoclasts, bone degrading cells, and osteoblasts, bone forming cells (Figure 23.2) [3, 76–78]. Osteoclasts are formed from monocyte/macrophage precursors in response to RANKL and monocyte colony stimulating factor (M-CSF) [81–82]. Osteoclast differentiation, fusion to form multinucleated cells, and activation result from 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. IL-6 is produced by monocyte/macophages and fibroblasts and enhances the recruitment of osteoclast precursors, promoting osteoclast formation (osteoclastogenesis) [79–80]. 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 RONS are released. Proton pumps produce an acidic pH, causing hydroxyapatite, the mineral making up the bone, to be dissolved.

23.7  Current considerations based on more recent findings and approaches to tissue analysis Recent findings suggest that IL-1, IL-1, and TNF- are not found in freshly retrieved human periprosthetic tissues and that the alternative macrophage activation pathway resulting in IL-8 and macrophage inflammatory protein (MIP)1 release, decreased local osteoprotegerin (OPG) levels, and impaired osteogenesis may be involved in periprosthetic osteolysis [28–29]. Many of the early studies evaluated the production of cytokines by periprosthetic tissues in culture. However, the recent comparative findings of Shanbhag et al. [29] show 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. 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. The authors suggest that the presence of TH1 cell chemoattractants imply a role for these cells in the inflammatory process. IL-8 is produced by several cell types and

Chapter  |  23  Pathophysiologic Reactions to UHMWPE Wear Particles

is chemotatic for T cells and neutrophils, and it also promotes angiogenesis (blood vessel formation) and osteoclast differentiation [79–80]. Current studies are focused on standardizing the tissue analysis and incorporating new molecular techniques to unravel the complex pathways involved in UHMWPE wear mediated inflammation and subsequent pathophysiologic changes.

23.8  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 [83–84]. The major reason for this oversight is that subclinical infection is very difficult to diagnose. In revision cases when infection is suspected, clinical laboratory tests are performed, which include tissue or joint aspirate bacterial cultures, peripheral blood ESR, WBC and differential, and levels of C-reactive protein [85]. However, all of the current approaches, including bacterial cultures and PCR for bacterial species, in joint implant biology and in other clinical areas, have so far proved to be inadequate [86–88]. Recently, Schroeder, et al. established a histomorphological criteria, in conjunction with polarized light microscopy, to define four types of periprosthetic membranes: periprosthetic membranes with wear debris (type I), periprosthetic membranes with infection (type II), periprosthetic membranes of combined types I and II (type III), and periprosthetic membranes with no obvious wear debris or infection (type IV) [84]. Both the interobserver reproducibility (95%) and the correlation between histopathologic and microbiologic diagnoses (89%, p  0.001) were higher than any of the previous approaches employed. Most notable was that the four types of periprosthetic membranes were observed at significantly different times of revision. This new classification system allows for a standardized diagnostic approach and future studies concerning the etiology and pathogenesis of THR revisions [84]. If infection is present, activation of macrophages can occur in response to several bacterial products, lipopolysacchride (LPS, gram negative bacteria), lipoteichoic acid, and peptidoglycan (gram positive bacteria) [88]. These products tend to adhere to UHMWPE and metal wear debris [89]. In vitro, the presence of LPS increased osteoclast formation and bone resorption in response to wear debris by 50–70%. Therefore, the presence of subclinical infection has the potential to greatly increase the host response to the generation of wear debris. In addition, the presence of bacterial products on the wear particles may reduce the threshold required for the initiation of pathophysiologic changes in the periprosthetic tissue and bone.

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23.9  Comparative pathophysiologic changes in periprosthetic hip tissues from historical and highly crosslinked uhmwpe implant retrievals To date, studies performed on periprosthetic tissue have largely focused on inflammatory factors that contribute to implant loosening. These studies, while informative, have been performed, for the most part, on tissues retrieved from patients receiving historical, gamma airsterilized UHMWPE components. The current generation of implants, however, are composed of newer, highly crosslinked UHMWPE material. To provide a context of differences between the osteolytic potential of wear debris from historical and highly crosslinked UHMWPE materials, we compared pathophysiologic changes in periprosthetic hip tissues. Unfortunately, because gamma air-sterilized UHMWPE material is no longer used, the retrieved historical components have a significantly higher implantation time as compared to the highly crosslinked components. While this is of concern, we believe that providing a context related to differences in the pathophysiologic tissue responses at the time of revision is very valuable in obtaining a better understanding of implant longeveity. In this study, bright field microscopic images of H&E stained tissue sections were evaluated for inflammatory cell infiltration, foreign body giant cells (GCs), histiocytes, necrosis, and fibrocartilage. A corresponding polarized light microscopic image of each tissue section was also analyzed to determine the presence of relatively small (0.5–2 m) and large (2 m) UHMWPE particles and to provide an evaluation of the histomorphology in the regions associated with wear debris. We believe this analysis provided a unique comparison of the pathophysiologic tissue responses highlighted in the previous sections for the historical UHMWPE components. In our comparison of historical and highly crosslinked UHMWPE component tissue histomorphology, we showed more prevalent and extensive inflammation, histiocytosis, necrosis, and wear debris in tissues retrieved from gamma air-sterilized UHMWPE hip implants. The presence of inflammation and histiocytes correlated with the accumulation of small UHMWPE wear debris (0.5–2 m), and GCs were consistently found near large UHMWPE particles (2 m). In addition, the presence of histiocytes and small wear debris correlated with focal regions of tissue necrosis. Our finding that the presence of histiocytes with ingested small wear debris and GCs associated with large wear debris from historical implant components are in agreement with those reported by others [91–93]. These findings are consistent with inflammatory-mediated histomorphic changes of periprosthetic tissue associated with

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phagocytosis of a continuous influx of UHMWPE wear particles, cellular activation, and production of cytokines and chemokines, ultimately resulting in cell death and focal necrosis of the tissues [61]. Collectively, these factors can contribute to tissue dysfunction, pain, osteolysis, and implant loosening. For the highly crosslinked cohort of patients, inflammation and necrosis were the most consistent findings, although histiocytes were observed in the majority of these patient tissues. The presence of histiocytes, without measureable wear debris, suggested that wear debris below the 0.5 m detection limit might be present. Tissue from several patients also contained metal and fibrocartilage, suggesting that micromotion of the femoral stem may contribute to metal wear generation and fibrocartilage formation. In general, our observations imply that the overall tissue response to wear debris and/or mechanical stimuli directly contribute to implant loosening of both gamma air-sterilized and highly crosslinked UHMWPE component hip implants, and these factors may ultimately result in the need for revision surgery. As the highly crosslinked UHMWPE components are retrieved with increasing times of implantation, we will have the opportunity to perform a more direct comparison of the pathophysiologic tissue response between the historical and highly crosslinked UHMWPE component implants, providing more conclusive answers to the question of biological compatibility.

23.10  Conclusion This chapter summarizes the current understanding of both the morphologic and inflammatory-related tissue changes that result from the generation of UHMWPE wear debris. The overall tissue response to wear debris is both complex and patient specific. However, the limitations of earlier methods of tissue preservation and in vitro and in vivo model systems are being increasingly recognized. In addition, technological methods for tissue analysis are continually being updated, such as 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 highy crosslinked UHMWPE 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 provide insight into the early diagnosis and treatment of inflammatory mechanisms involved in the loss of implant function.

23.11  Acknowledgments The research outlined in this chapter was supported by NIH R01 AR47904.

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