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J Am Acad Orthop Surg, Vol 16, No suppl_1, July 2008, S49-S55.
© 2008 the American Academy of Orthopaedic Surgeons
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How has the biologic reaction to wear particles changed with newer bearing surfaces?

Joshua J. Jacobs, MD, Patricia A. Campbell, PhD and Yrjö T. Konttinen, MD, PhD

Dr. Jacobs is Professor and Chairman, Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL. Dr. Campbell is Director, Implant Retrieval Lab, J. Vernon Luck Sr. MD Orthopaedic Research Center, UCLA-Orthopaedic Hospital, Los Angeles, CA. Dr. Konttinen is Professor of Medicine, Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland.

*The Implant Wear Symposium 2007 Biologic Work Group included Thomas W. Bauer, MD, PhD, Joan Bechtold, PhD, Mathias Bostrom, MD, Patricia A. Campbell, PhD, Victor Goldberg, MD, Stuart B. Goodman, MD, PhD, Ed M. Greenfield, PhD, Joshua J. Jacobs, MD, Yrjö Konttinen, MD, PhD, Regis O’Keefe, MD, PhD, Francis Young-In Lee, MD, Edward M. Schwarz, PhD, Arun S. Shanbhag, PhD, MBA, Robert Lane Smith, PhD, Rocky S. Tuan, PhD, and J. Mark Wilkinson, PhD, FRCS(Tr&Orth).

Dr. Jacobs or a member of his immediate family has received research or institutional support from Zimmer, Wright, Medtronics, Spinal Motion, Archus, and AST, and is a consultant for or an employee of Zimmer, Wright, Medtronics, Spinal Motion, Archus, and AST. Dr. Campbell or a member of her immediate family has received research or institutional support from DePuy, Smith & Nephew, and Wright Medical Technology. Neither Dr. Konttinen nor a member of his immediate family has received anything of value from or owns stock in a commercial company or institution related directly or indirectly to the subject of this article.


   Abstract
Top
 Abstract
The Biology of Wear...
 Immune Response
 Future Directions for Research
 Figures
 References
 
Orthopaedic surgeons have new tools that address the problem of aseptic loosening and osteolysis, and these tools are now in widespread clinical use. Hard-on-hard bearing couples as well as metal-on–highly cross-linked polyethylene bearing couples have lower volumetric wear rates and represent promising solutions to reduce the prevalence of osteolysis and aseptic loosening in total joint arthroplasty. Volumetric wear rates alone, however, do not completely predict the osteolytic potential that is also a function of particle composition, size, morphology, and a number of other particle characteristics. Host factors, including differing innate reactivities to wear products and adaptive immune responses, remain important but incompletely defined. Although the toxicologic significance of local and systemic elevations in metal ions has not been definitively established, monitoring patients with metal-on-metal bearings with serum metal ion levels can be useful to determine the state of the bearing. Furthermore, optimization of these bearing systems to further diminish wear and corrosion would be highly desirable.

The armamentarium of the adult reconstructive surgeon has expanded considerably in recent years, with increasing choices of articulating couples used in total joint arthroplasty. Although the current material options for bearing couples have been around for decades, there have been refinements in material processing such that the current generation of bearing materials is reflective of the advanced technology that is available today. Specifically, the orthopaedic surgeon now has available highly cross-linked ultra-high–molecular- weight polyethylene bearing surfaces, ceramic-on-ceramic bearing surfaces, and metal-on-metal bearing surfaces that all promise to reduce volumetric wear and, it is hoped, reduce the long-term complications of osteolysis and aseptic loosening. In this update, the state of the science will be reviewed with particular emphasis on the biologic reactions associated with the degradation products of modern hip arthroplasty bearing couples.

In the 1990s, there was a clear rationale for the development of improved bearing surfaces—that is, there was a high prevalence of late osteolysis and aseptic loosening associated with the bearing couples used at that time, particularly in the high-demand patient population. Furthermore, there was an increasing understanding throughout the late 1980s and early 1990s that the host response to particulate wear debris1,2 and modular junction fretting corrosion products3,4 were major factors in the etiology of periprosthetic osteolysis and aseptic loosening. Thus, the current generation of bearing couples was developed with the goal of reducing volumetric wear, which would in turn reduce the prevalence of osteolysis and aseptic loosening. A critical question that can be posed is whether the reduction of volumetric wear is sufficient to achieve the desired reductions in osteolysis and aseptic loosening.


   The Biology of Wear Debris From Newer Bearing Materials
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 The Biology of Wear...
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To answer this question, it is illustrative to review what is known about the basic biology of osteolysis and aseptic loosening. Studies from implants performed in the 1980s and 1990s indicate that a vast majority of wear debris surrounding failed joint arthroplasties is polyethylene and that >90% of the particulate polyethylene debris is <l µm in size, with a mean particle size being on the order of 0.5 µm.5,6 Further in vitro studies have established that the cell response to particulate debris is a function of the size, composition, and dose of the particles.7 This can be considered a fundamental precept of cell/particle biology. Other more subtle factors that may influence particulate biocompatibility include the aspect ratio, surface roughness of the particles, and the composition of absorbed proteins, which are currently less completely understood.8

It is important to understand the factors of particulates that are key in eliciting the biologic response in an effort to predict the long-term behavior of the so-called alternative bearings. For example, investigators have examined debris produced from highly cross-linked polyethylene. Recent reports have suggested that highly cross-linked polyethylene debris tends to be smaller and may be more bioreactive;9 however, this effect may be overcome by a substantially reduced clinical volumetric wear rate. Conducting such in vitro studies is challenging, given the difficulties in fabrication or isolation of pure populations of submicron-sized polyethylene particles.

For metal-on-metal bearings, the volumetric wear rate has been shown to be more than an order of magnitude smaller than that associated with metal-on-polyethylene bearings. However, the particle size of the debris generated from metal-on-metal bearings is approximately an order of magnitude smaller, in the nanometer-size range.10 The net effect is that, even though the volumetric wear rates are lower with metal-on-metal bearings, the actual number of particles generated from metal-on-metal wear greatly exceeds that from metal-on–conventional polyethylene wear,10 and the resulting specific surface area (surface area/mass) is extensive. Thus, to characterize the biocompatibility of particulate debris from metal-on-metal bearings, one needs to understand the bioreactivity difference between 0.5-µm polyethylene particles versus 50-nm (0.05-µm) cobalt-chromium alloy particles and their corrosion products. Given the difficulty of fabrication and isolation of nanodebris to use in cell challenge studies, this question is still an active area of scientific investigation.

Regarding ceramic debris, there is a body of literature demonstrating the reactivity of submicron-size ceramic particles. Ceramics in bulk form are inert in that they do not undergo oxidative environmental degradation. However, in submicron-size particulate form, alumina and zirconia ceramics can elicit cell responses that are similar in character and intensity to those elicited from submicron-size polymeric and metal debris.11,12 For example, poorly functioning ceramic-on-ceramic total hips have been associated with osteolysis when excessive amounts of ceramic particulate debris present in the periprosthetic tissues caused a fibrohistiocytic response.13 In addition, the retrieved particles were of a mean size of 0.7 µm, similar to that seen with polyethylene debris.13 Unlike metallic wear products from metal-on-metal bearings, particles from the various ceramic biomaterials do not undergo electrochemical dissolution (corrosion) and are generally thought to be nonstimulatory to the adaptive immune system. The wear volume is generally significantly less than that with metal bearings, and the periprosthetic cellular response to wear particles of alumina ceramic appears to be determined by the same biologic factors that govern the response to particles of other biomaterials—that is, size, shape, and volume. Particle size is reportedly bimodal; most particles are nanometer-size, with the remainder being submicron- to micron-size. It seems that the low volume of debris generated from well-functioning alumina ceramic bearings is unlikely to produce an osteolytic response. Reports of a mostly fibrotic reaction in tissues recovered from hips with low-wearing alumina-on-alumina bearings support this. In sufficient quantities, as occurs with damaged or poorly functioning total joint components, alumina ceramic particulate induces biologic responses similar to those induced by polyethylene, including osteolysis.14 The biologic response to zirconia ceramic particles seems to be comparable to that of alumina particles with similar morphologic features.12

Metal-on-metal bearings have seen tremendous resurgence, particularly with the current interest in resurfacing arthroplasty of the hip. The concerns with metal-on-metal bearings are somewhat different than those with ceramic-on-ceramic or metal-on-polyethylene, given the nature and characteristics of wear and corrosion debris that can be produced by these articulating surfaces. In addition to generating particulate wear debris, metal-on-metal bearings can also generate free metallic ions that can subsequently interact with proteins or anions in the local body fluids and intracellularly in phagocytes, producing organometallic complexes or inorganic metal salts or oxides. Thus, all of these degradation products need to be considered when trying to understand the host response to metallic debris.

As noted above, previous studies have shown that most of the metallic particulate debris in vivo is <50 nm in size, producing particles at a higher rate than do metal-on-polyethylene bearings, which have higher volumetric wear rates but much larger particle sizes. It is the presence of very large numbers of nanodebris with high specific surface areas that is largely responsible for the release of metal ions into the surrounding tissues and subsequently into serum and urine. Several investigators have documented order of magnitude elevations in serum and urine cobalt and chromium in patients with metal-on-metal bearings.15-17 In some studies in patients with long-term metal-on-metal bearings, these elevations seem to persist throughout the duration of implantation.15 Acute toxicity from these elevated levels is extraordinarily rare; however, there are ongoing questions about potential chronic toxicity in association with chronic elevations in circumstances such as renal failure, where cobalt and chromium degradation products cannot be cleared. Local accumulation of wear and corrosion products in joint fluid can lead to highly elevated ion levels. Along with other biomaterials used in total joint arthroplasties, cobalt-chromium alloy debris has been shown to induce chromosomal aberrations in human and animal cells, but the clinical implications of these observations are unclear.18


   Immune Response
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 Abstract
 The Biology of Wear...
 Immune Response
Future Directions for Research
 Figures
 References
 
Metal-on-metal wear produces mostly nanometer-size particles that can corrode and become detectable in the blood and urine as metal ions. The processes involved in the formation of metal wear products and potentially antigenic haptens are poorly understood. The various corrosion products vary in size, stability, and solubility, and consequently in their bioavailability and inflammatory and immunogenic potentials. Particle aggregates and larger particles interact with the phagocytic cells, causing release of potentially osteolytic cytokines. Wear products from metal-on-metal hips are associated with B and T lymphocytes as well as plasma cells. There are occasional reports of extensive necrosis, enlarged bursae, and groin masses19,20 occurring around metal-on-metal joints, but whether these are caused by elevated levels of wear or corrosion products or by patient hypersensitivity is unclear.21,22 Figure 1 shows the complex interrelationship between the wear products and cells of the innate and adaptive immune systems.


Figure 1
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  		Figure 1 Complex interrelationship between wear products and cells of the innate and adaptive immune systems. GM-CSF = granulocyte monocyte-colony stimulating factor, IFN = interferon, IL = interleukin, MCP = monocyte chemoattractant protein, PDGF = platelet-derived growth factor, PGE2 = prostaglandin E2, RANK = receptor activator of nuclear factor {kappa} B, RANKL = receptor activator of nuclear factor {kappa} B ligand, TC = cytotoxic T lymphocyte, TGF = transforming growth factor, TH = T helper lymphocyte, TNF = tumor necrosis factor

 
One area that is of particular interest currently is the role that metal allergy may play in clinical performance of metal-on-metal devices. Metal allergy is a phenomenon that has been of interest to the orthopaedic community for decades. The literature supports the fact that metal allergy is a real clinical phenomenon, although the prevalence and clinical impact are not defined.23,24

Degradation products, either in the form of ionic or particulate debris, can complex with local proteins, which alters their confirmation and elicits an allergic response comparable with a delayed-type hypersensitivity response (type IV). This type of hypersensitivity is mediated by T lymphocytes reactive against metal ion–modified self-proteins. These cells have thus been sensitized against the metal ion or hapten-modified self-proteins, which in that instance must have been processed and presented by major histocompatibility complex class II molecules to the epitope-specific T-cell receptors. This provides the primary stimulus to the immune response. If this stimulus occurs alone, the T lymphocytes may undergo apoptosis and become anergic or develop into regulatory T lymphocytes downregulating immune responses against the antigen in question.

To respond with an immune response, the T lymphocyte must also get a secondary stimulus. This is provided by danger-associated molecular patterns (DAMPs), which can be exogenous microbial pathogen-associated molecular patterns (PAMPs) or endogenous alarmins, such as monosodium urate crystals, which form upon release from damaged cells. The secondary stimulus is classically provided by costimulatory molecules, which are classified into soluble and cell membrane–bound costimulatory molecules. Tumor necrosis factor-{alpha} and interleukin-1 are released by the antigen-presenting cell, and interferon-{gamma}, by the T lymphocyte. Cell membrane–bound costimulatory molecules include, for example, B7-1 and B7-2 on the surface of the antigen-presenting cell binding its counter ligand CD28/CTLA4 (cluster of differentiation 28 antigen/cytotoxic T-lymphocyte antigen 4) on the surface of the lymphocyte, with intercellular adhesion molecule (ICAM)-1 and lymphocyte function–associated antigen (LFA)-1, as well as lymphocyte function–associated antigen (LFA)-3 and cluster of differentiation 2 (CD2) antigen forming similar ligand-counterligand pairs.

When the T lymphocyte is responding to both primary and secondary stimulus, it will become sensitized, starting antigen-driven clonal proliferation and differentiation. These costimulatory molecules also induce maturation of the antigen-presenting dendritic cells. In patients with joint implants, one possible stimulus to induce optimal upregulation of such costimulatory molecules is formed by highly conserved microbial structures (pathogen-associated molecular patterns), which are able to stimulate Toll-like receptors (TLRs) and provoke innate immunity. TLRs usually sense pathogen invasion as their ligands derive from microbes. However, endogenous TLR ligands have been recognized, the best-characterized of them being urate crystals.25 At the same time, the TLR-evoked response helps to establish the adaptive immune response.26 This represents an example of cooperation between innate and adaptive immunity.

There is some evidence that patients with metal-on-metal bearings and/or high serum metal levels elicit more response to metal antigen challenge measured as either patch-test sensitivity or lymphocyte proliferation.22 Thus, while there is an idiosyncratic aspect of the allergic response, there may also be a dose-response component.

Clinical testing for implant-associated metal allergy is, unfortunately, not straightforward, and there is currently no gold standard test for diagnosis. Historically, patch testing is the most common means to assess metal hypersensitivity. Although this modality is quite helpful to characterize cutaneous hypersensitivity, it is less clear how the observed responses relate to allergic responses in the periprosthetic milieu. For example, the skin possesses unique antigen-presenting cells (Langerhans cells) that are not present in the periprosthetic tissues. In addition, it is unclear which are the optimal challenge agents (eg, metal chlorides, specific metal-protein complexes). Furthermore, patch testing provides only qualitative results, which have not correlated well with clinical performance of devices. In vitro testing for metal allergy takes advantage of the fact that antigen-challenged sensitized lymphocytes change their behavior by secreting characteristic cytokines,27,28 altering their migration patterns, and by proliferating. The latter is relatively easy to measure using 3H thymidine incorporation, forming the basis for the lymphocyte transformation test (LTT) that measures the ratio of lymphocyte proliferation after antigen challenge to lymphocyte proliferation in the absence of antigen. This ratio is called the stimulation index (SI).

The advantage of LTT testing is that it bypasses the skin and provides a quantitative measure of reactivity in the SI. However, the role of this modality in clinical testing remains uncertain because, as is the case in patch testing, the optimal challenge agent has yet to be established. Also, methods and interpretation of results are difficult to standardize among laboratories. In addition, "threshold" values for the SI are unknown, and clinical correlations have yet to be established. In one study using LTT to characterize the lymphocyte reactivity in patients undergoing total hip replacement, positive responders to nickel (with a threshold value of SI set at 2.0) were far more likely to have a history of sensitivity to metal jewelry, providing some validation for this assay. Interestingly, patients with total hip replacements and radiographic evidence of osteolysis were more likely to demonstrate sensitivity to chromium (SI >2.0) compared with patients without evidence of osteolysis.29 This suggests a role for the adaptive immune response in the pathogenesis of osteolysis.

Recent studies have reported a unique histologic response in patients with metal-on-metal bearings in which there is a prominent perivascular and/or diffuse lymphocytic infiltration that is reminiscent of a delayed-type hypersensitivity response (Figure 2). This response has been termed aseptic lymphocyte-dominated vasculitis-associated lesion (ALVAL) by Willert et al,30 and it is reported around metal-on-metal implants from various manufacturers. This response is not completely understood; the incidence of individuals requiring revision for an apparent hypersensitivity to otherwise well-functioning metal-on-metal bearings is currently unknown, but it is thought to be relatively low. Recent clinical reports have suggested a link between early osteolysis in patients with metal-on-metal bearing total hip replacement systems and metal hypersensitivity, based on either patch testing or histologic evidence of ALVAL.30-35 This is an area that will require ongoing investigation.


Figure 2
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  		Figure 2 A, Low-power overview of periprosthetic tissue from a patient with a metal-on-metal hip replacement revised for suspected metal sensitivity. Note the adherent fibrin and focal accumulation of lymphocytes deep to the surface, separated by a wide zone of partially necrotic material. B, Very dense accumulations of lymphocytes that typify the periprosthetic tissues of patients revised for metal sensitivity. C, Higher-power micrograph showing dense aggregates of diffuse and perivascular lymphocytes that are also a common feature of tissues from patients revised for metal sensitivity. Plasma cells are often present in these aggregates. (Courtesy of Nadim Hallab, PhD.)

 
However, it is becoming clear that metal-on-metal implants that are malfunctioning and that produce high wear can create wear products that elicit pain, effusions, and, in some cases, osteolysis. It is likely that the performance of metal-on-metal bearings will be design-specific, related to clearance, metallurgy, geometry, and the presence of modular interfaces.

Orthopaedic surgeons have new tools that address the problem of aseptic loosening and osteolysis; these tools are now in widespread clinical use. Hard-on-hard bearing couples as well as metal-on–highly cross-linked polyethylene bearing couples have lower volumetric wear rates and represent promising solutions to reduce the prevalence of osteolysis and aseptic loosening in total joint arthroplasties. Volumetric wear rates alone, however, do not completely predict the osteolytic potential that is also a function of particle composition, size, morphology, and a host of other particle characteristics. Host factors, including differing reactivities to wear products, remain important but are not clearly defined. Although the toxicologic significance of elevated metal ions has not been established, monitoring patients with metal-on-metal bearings with metal ion levels can be useful to determine the state of the bearing surfaces. Furthermore, optimization of these bearing systems to further diminish wear and corrosion would be highly desirable.


   Future Directions for Research
Top
 Abstract
 The Biology of Wear...
 Immune Response
 Future Directions for Research
Figures
 References
 
Ultimately, the biologic reaction to debris generated from bearing surfaces may well govern the survivorship of contemporary total joint replacements. Detailed mechanistic studies of the pathogenesis of periprosthetic osteolysis and implant loosening are needed to more fully characterize the features of implant debris that are the most critical in determining the biologic response. In particular, there is very little information on the bioreactivity of nanodebris and the nature of the biofilm adherent to particulate wear and corrosion products. Further delineation of the molecular pathways involved in osteolysis and aseptic loosening is required to identify therapeutic targets for modification of the host response to implant debris. In turn, pharmacologic agents that may be of benefit in modifying this host response need to be evaluated in animal models and, if appropriate, in human clinical trials. Individual variability in host response, arising from either constitutive differences in innate immune responses or by adaptive immune processes, needs to be investigated because this may lead to novel preoperative screening protocols that may predict the risk of adverse biologic responses to specific types of debris. Clinical and histopathologic validation of in vitro and epicutaneous methods of diagnosing metal hypersensitivity are urgently needed to provide the practitioner with a clinically reliable tool to evaluate the symptomatic patient following a total joint replacement when metal hypersensitivity is in the differential diagnosis. Finally, epidemiologic studies addressing the possible long-term systemic effects of implant debris are needed.


   Figures
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 The Biology of Wear...
 Immune Response
 Future Directions for Research
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   References
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 The Biology of Wear...
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  1. Harris WH: The problem is osteolysis. Clin Orthop Relat Res 1995; 311:46-53.[Medline]
  2. Jacobs JJ, Roebuck KA, Archibeck M, Hallab NJ, Glant TT: Osteolysis: Basic science. Clin Orthop Relat Res 2001; 393:71-77. [Medline]
  3. Urban RM, Jacobs JJ, Gilbert JL, Galante JO: Migration of corrosion products from modular hip prostheses: Particle microanalysis and histopathological findings. J Bone Joint Surg Am 1994; 76:1345-1359. [Abstract/Free Full Text]
  4. Lee SH, Brennan FR, Jacobs JJ, Urban RM, Ragasa DR, Glant TT: Human monocyte/macrophage response to cobalt-chromium corrosion products and titanium particles in patients with total joint replacements. J Orthop Res 1997; 15:40-49. [ISI][Medline]
  5. Shanbhag AS, Jacobs JJ, Glant TT, Gilbert JL, Black J, Galante JO: Composition and morphology of wear debris in failed uncemented total hip replacement. J Bone Joint Surg Br 1994; 76:60-67. [Medline]
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  7. Shanbhag AS, Jacobs JJ, Black J, Galante JO, Glant TT: Human monocyte response to particulate biomaterials generated in vivo and in vitro. J Orthop Res 1995; 13:792-801. [ISI][Medline]
  8. Hallab NJ, Skipor A, Jacobs JJ: Interfacial kinetics of titanium- and cobalt-based implant alloys in human serum: Metal release and biofilm formation. J Biomed Mater Res A 2003; 65:311-318. [Medline]
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