Wear particulate and osteolysis

Orthop Clin N Am 36 (2005) 41 – 48

Wear particulate and osteolysis Stuart Goodman, MD, PhD, FRCSC Department of Orthopaedic Surgery, Stanford University Medical Center, 300 Pasteur Drive, Stanford, CA 94305, USA

Joint prostheses stabilized with polymethylmethacrylate Implants for total joint replacement must contribute to a biologically favorable and mechanically stable environment to provide a satisfactory longterm clinical outcome. Mechanically loose prostheses undergo excessive displacement with the application of physiologic loads; histologically, these events lead to a reactive fibrotic interface that may demonstrate a synovial lining layer [1 – 5]. This is true for implants that are cemented, cementless, and those covered by bioactive coatings. Cemented implants for joint replacement are still the gold standard by which all others are compared. The use of polymethylmethacrylate bone cement is part of a concept referred to as composite fixation, ie, the metallic or polymeric implant is stabilized by the addition of cement. In the case of polymethylmethacrylate, prosthetic stabilization is afforded by a mechanical interlock between the cement and the bony interstices [1]. In this manner, the cement acts as a grout with no adhesive properties. Polymethylmethacrylate for use in joint replacement has many advantages: It increases the biomechanical stability of the reconstruction It decreases the stress on the primary implant It facilitates early weightbearing and rehabilitation

This work has been supported in part by grants from the Stanford Orthopaedic Research Laboratory and Zimmer. E-mail address: [email protected]

It rapidly cures within approximately 10 – 20 minutes It can provide a delivery system for antibiotics It is easy to handle and deliver It is currently in common use It is inexpensive Polymethylmethacrylate has several shortcomings, however, including the following: It is strong in compression but far weaker in tension, bending, and torsion It may undergo fatigue fracture It is chemically dissimilar from bone It cures by way of an exothermic reaction It contracts when it cures, then slowly expands because of absorption of water It is nonbiodegradable and nonremodelable It is nonosteoinductive and nonosteoconductive It may interfere with fracture healing The monomer demonstrates cellular toxicity There may be an allergic reaction to certain of its constituents Particles generate a chronic inflammatory and foreign body reaction Despite its widespread use and documented clinical success, polymethylmethacrylate thus has some major shortcomings. Indeed, one of the major long-term problems with the use of polymethylmethacrylate is loosening and periprosthetic osteolysis secondary to cement fragmentation and the inflammatory and foreign body reaction to wear debris [6]. This outcome has been termed cement disease, but in reality it is part of a more comprehensive process called particulate disease (Fig. 1).

0030-5898/05/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ocl.2004.06.015

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S. Goodman / Orthop Clin N Am 36 (2005) 41 – 48

Particulate disease Currently the most important issue regarding total joint replacement is prosthetic wear and the adverse biologic reaction to wear debris and its byproducts [7]. Debris from articulating and nonarticulating surfaces of implant systems, the surrounding bone, and other structures accumulates locally and incites a foreign body and chronic inflammatory reaction composed primarily of macrophages and foreign body giant cells in a fibrous stroma [2,3,8 – 11]. These circumstances begin a cascade of events culminating in periprosthetic bone resorption, which further undermines the prosthetic bed. With intermittent loading, waves of increased pressure within the joint distribute the wear particles and byproducts, cellular constituents, and inflammatory mediators to more remote sites along the bone – implant interface and beyond [12].

Histology of prosthetic loosening and osteolysis Gross examination of the interface surrounding loose cemented joint arthroplasties yields a thick, tan colored, pliant tissue that is composed of mono- and multinucleated foreign body cells (macrophages) and

Fig. 1. Cement disease. Anteroposterior radiograph of a hybrid total hip prosthesis. There is fragmentation of the bone cement around the femoral component, severe periprosthetic osteolysis, and prosthetic subsidence.

chronic inflammatory cells in a fibrous stroma [8,9]. Goldring et al described the presence of a synoviallike lining layer on the membrane surface, adjacent to the cement layer [2,3]. This 1 – 2-cell layer is composed of large polygonal cells with eccentric nuclei located away from the cement surface. This synovial-like layer is supported by a loose fibrovascular stroma containing macrophages and wear particles. A third layer of more dense fibrous tissue supports the second layer and abuts the surrounding bone. Particles of polymethylmethacrylate, polyethylene, and metallic debris, depending on the materials in the implant, are found within the periprosthetic tissues. Polymethylmethacrylate normally is dissolved during routine processing of the tissue specimens. Its presence can be identified, however, by the large voids or cement lakes 100 – 1000 mm in diameter, the round vacant cement ‘‘ghosts’’ 5 – 80 mm in diameter, and the presence of smaller residual, undissolved 0.5 – 1-mm barium sulfate particles or other radio-opaque material. Polyethylene debris is generally more widespread within the stroma; small particles usually less than 1 – 2 mm in diameter are phagocytosed by macrophages, fibroblasts, and other cells; larger shards greater than 10 mm in diameter are surrounded by numerous multinucleated giant cells in a fibrous stroma [10]. Polyethylene debris can be identified best with the use of polarized light or oil red O staining methods [13]. Debris from metal alloys form black intra- and extracellular specks, visible by light microscope and in the micron or submicron range. If metallic wear has been excessive, the tissues may have a black discoloration on gross examination. Wear particles from ceramic prostheses are much smaller in size and fewer in number compared with polyethylene particles and seem to be more benign. Tissues from loose cementless implants are usually less abundant, more fibrous, and, of course, do not contain polymethylmethacrylate debris [4]. The cellular response to wear particles is designated a chronic inflammatory and nonspecific foreign body reaction. In a small subset of patients, however, there may be a type IV cellular immune reaction to the particle – protein complex [14]. This reaction may be to protein-coated particles of polymers, metals, or other materials, but emphasis has been more on the metallic constituents. Histologically, this manifests as infiltrates of T lymphocytes in the tissues with perivascular lymphocytic cuffing. Indeed, particles from revised metal-on-metal articulations that have been introduced more recently were reported by Willert et al to be associated with a diffuse and perivascular lymphocytic infiltrate and swelling and

S. Goodman / Orthop Clin N Am 36 (2005) 41 – 48

obliteration of blood vessel walls [15]. Five to ten percent of the lymphocytes expressed the proliferation-associated antigen Ki-67. These findings are suggestive of a cell-mediated immune reaction. Of interest, this reaction also seemed to be of a much higher intensity compared with older metal-on-metal prostheses retrieved during revision surgery. The aggressive granulomatous reaction refers to a radiographic finding in which progressive, locally expanding periprosthetic osteolytic lesions are seen around a joint replacement [16]. The presence of activated fibroblasts and macrophages are seen using special immunohistochemical staining. It has been hypothesized that this phenomenon may be caused by an uncoupling of the events encompassing the nonspecific foreign body response and reactive fibrosis [16].

The proinflammatory cascade and mediators of osteolysis Cellular and molecular biologic techniques, including histochemistry, immunohistochemistry, in situ hybridization, polymerase chain reaction (PCR), and Western and Northern blot analysis have yielded important information on the biologic processes in the periprosthetic tissues [17 – 26]. Activated macrophages from the periprosthetic tissues express the proinflammatory cytokines interleukin-1, interleukin-6, and tumor necrosis factor alpha; these cytokines play a major role in the process of periprosthetic osteolysis [27,28]. Increasing numbers of activated macrophages have been shown to correlate highly with the prevalence of particulate debris, especially polyethylene particles [29,30]. Granulocyte-macrophage colony stimulating factor (GM-CSF), a growth factor that regulates the transformation of immature macrophages into multinucleated giant cells and osteoclasts, is highly expressed by phagocytic macrophages [31]. In areas of osteolysis, markers of bone formation (heightened alkaline phosphatase activity) on the surrounding bony surface are also highly prominent, indicating attempts at bone repair [32]. Transforming growth factor beta, an anti-inflammatory reparative cytokine, is also highly expressed by multinucleated giant cells of the pseudosynovium surrounding loose implants [33]. Proinflammatory cytokines that act primarily as chemoattractants for cells of the immune system are referred to as chemokines [21 – 26]. One subfamily of chemokines highly relevant to macrophage activation is the C-C chemokine group. The C-C chemokine subfamily consists of monocyte chemoattractant

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proteins-1, -2, -3, -4 (MCP-1, -2, -3, -4), macrophage inflammatory proteins-1a, 1-b, 3-a, 3-b (MIP-1-a, 1-b, 3-a, 3-b), and regulated on activation normal T expressed and secreted protein (RANTES). Retrieved periprosthetic tissues from prostheses demonstrating radiographic osteolysis demonstrated MCP-1 and MIP-1-a expression, but RANTES expression was not observed [25]. Expression of other chemokines also has been observed in retrieved tissues harvested from failed total joint arthroplasties using cellular and molecular techniques [29 – 31]. Numerous degradative enzymes, including matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) are highly expressed in tissues harvested from loose prostheses. These proinflammatory molecules include collagenases MMP-1, MMP-2, and MMP-9 gelatinases, stromelysin MMP-3, extracellular matrix metalloproteinase inducer (EMMPRIN), an MMP upregulator, cathepsin C, alpha 1-antichymotrypsin, tenascin, elastase, and so on [34 – 44]. Proinflammatory factors such as the prostanoids and leukotrienes, especially prostaglandin E2, and nitric oxide metabolites are also highly expressed [2 – 4, 45,46]. These degradative enzymes and other factors are important in the cascade of events leading to osteolysis and the undermining of the bony support of an implant. Biomaterial particles not only stimulate macrophages but also activate T lymphocytes in the presence of a suitable antigen (a protein-coated particle) and costimulatory molecules such as CD80 and CD86. Immunochemical studies recently have confirmed the presence of this pathway, indicating the importance of T lymphocytes and immune processes in the periprosthetic tissues [47,48]. The exact role of T cells and related immune processes in modulating the periprosthetic events is controversial, however. The osteoclast is the final common pathway in effecting periprosthetic bone resorption. Osteoblasts and stromal cells, however, are integral parts of this process by releasing the receptor activator of nuclear factor-kappa B ligand (RANKL), also known as osteoprotegerin ligand (OPGL), which together with M-CSF is essential for osteoclast differentiation from monocytes/macrophages. Osteoprotegerin (OPG), the soluble receptor for RANKL, inhibits the pathways mentioned previously. Studies of tissues retrieved from failed joint arthroplasties have noted an imbalance in the RANK-RANKL-OPG system, which may lead to excessive periprosthetic osteolysis [49 – 52]. The exact mechanisms, however, are controversial because of the redundancy in the inflammatory cascade, including the final common pathway for activation of osteoclasts [50].

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Cement disease: fact or fiction Animal studies have shown that cement particles can produce a foreign body and chronic inflammatory reaction that is histologically similar to that seen around loose cemented implants in humans (Fig. 2) [53]. In one animal model, cement particles decreased net bone formation because of a combination of decreased bone formation and increased bone resorption (Fig. 3) [54]. In this model, however, inhibition of bone formation was more pronounced with polyethylene particles compared with cement particles [54]. Polyethylene particles in the submicron range have been shown to be more prevalent than larger (greater than 5 microns) polyethylene particles; moreover, smaller polyethylene particles are more biologically active and stimulate a greater release of proinflammatory cytokines [7,13,29,55].

In vivo and in vitro studies have confirmed that cement particles can activate the proinflammatory cascade, resulting in increased production of cytokines, prostanoids, metalloproteinases, and other factors associated with osteolysis [56 – 60]. In humans, cement debris may be generated from incomplete mixing of the monomer and polymer, from abrasion or fatigue fracture of the bone cement, and from third body wear. The resulting inflammatory and foreign body reaction leads to the insidious destruction of periprosthetic bone, with few symptoms and signs in the early stages [61]. Such cases may demonstrate little evidence of polyethylene wear. Radiographs often demonstrate deficiencies in the periprosthetic cement mantle. Infection may be suspected, but cultures of the interface tissue are negative. These cases demonstrate progressive osteolytic defects, and revision surgery becomes imminent, especially if there

Fig. 2. The histologic reaction to polymethylmethacrylate bone cement using the rabbit tibia model. (A) Bulk cement evokes a bland fibrous delimiting membrane at the cement – host interface. Remnants of bone cement can be seen above the tissue. Decalcified section stained with hematoxylin and eosin. (B) Particulate cement evokes a foreign body and chronic inflammatory reaction. Decalcified section stained with hematoxylin and eosin. (C) In this section, cement particles have evoked a granulomatous reaction with mono- and multinuclear macrophages and a delimiting thin fibrous encasement. Decalcified section stained with hematoxylin and eosin.

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Fig. 3. The histologic reaction to polymethylmethacrylate bone cement using the bone harvest chamber model. (A) After 3 weeks, the bone harvest chamber is filled with longitudinally oriented woven trabecular bone in a fibrovascular stroma. (B) If polymethylmethacrylate particles are placed in the bone harvest chamber for 3 weeks, the harvested tissue demonstrates a foreign body and chronic inflammatory reaction, fibrosis, and decreased ingrowth of bone compared with controls.

is associated prosthetic loosening (see Fig. 1). Although recent emphasis has been on polyethylene wear debris as the main culprit in particulate disease, cemented implants also may demonstrate progressive osteolytic defects caused by particulate cement. Recent in vivo and in vitro studies have implicated the small radiopaque particles of barium sulfate, zirconium oxide, and others as exacerbating the situation, although this is controversial [62 – 68]. Furthermore, a subset of patients demonstrate an allergic reaction to the accelerator in polymethylmethacrylate, N,N-dimethylparatoluidine (DMT) [69]. This manifests as a rapid onset (within a few years) of aseptic loosening, often with osteolytic lesions. Patch testing confirms a type IV allergic reaction in these patients.

Future studies Particulate disease is caused by the local and systemic biologic response to wear particles and byproducts from joint prostheses. Clearly if wear is decreased the production of wear debris and the subsequent biologic reaction should be mitigated. The task of further optimizing materials for total joint replacement must be a collaborative effort between surgeons, engineers, material scientists, biologists, and others. Despite the success of polymethylmethacrylate, some of its physical and chemical properties and associated biologic reactions may be improved, as outlined. In vitro and in vivo studies are now being performed to explore whether the biologic reaction to wear particles can be modulated

by pharmacologic interventions. These areas of research may lead to a better understanding of the processes of wear and particulate disease and to improved implant longevity.

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