7.8 Implant Debris: Clinical Data and Relevance☆

7.8 Implant Debris: Clinical Data and Relevance☆ NJ Hallab and JJ Jacobs, Rush University Medical Center, Chicago, IL, United States r 2017 Elsevier Ltd. All rights reserved.

7.8.1 7.8.2 7.8.2.1 7.8.2.1.1 7.8.2.2 7.8.2.2.1 7.8.2.3 7.8.2.4 7.8.2.4.1 7.8.2.4.2 7.8.2.4.2.1 7.8.2.4.2.2 7.8.2.4.3 7.8.3 References

Introduction Implant Debris Types: Particles and Ions Particulate Debris Particle characterization Metal Ions (Soluble Debris) Metal ion release Local Tissue Effects of Wear and Corrosion Systemic Effects of Wear and Corrosion Systemic particle distribution Hypersensitivity Incidence of hypersensitivity responses among patients with metal implants Testing for metal sensitivity Carcinogenesis Conclusions

PMMA Polymethylmethacrylate ppb Parts per billion (ng/mL or mg/L) PTFE Teflon (polytetraflouroethylene) RANKL Receptor activator of nuclear factor Kappa Beta ligand ROS Reactive oxygen species SEM Scanning electron microscopy TEM Transmission electron microscopy THA Total hip arthroplasty Ti Titanium TJA Total joint arthroplasty TJR Total joint replacement TNF-a Tumor necrosis factor – alpha UHMWPE Ultra high molecular weight polyethylene V Vanadium

Abbreviations Al Aluminum ALVAL Aseptic lymphocyte vasculitis associated lesion Co Cobalt Cr Chromium Cr(PO4)4H2O Chromium orthophosphate DAMP Danger associated molecular patterns IL-6 Interleukin 6 IL-18 Interleukin 18 IL-33 Interleukin 33 LALLS Low angle laser light scattering NALP3/ASC Inflammasome complex of proteins PAMP Pathogen associated molecular pattern PGE2 Prostaglandin E2

Glossary DTH Delayed type hypersensitivity adaptive (lymphocyte mediated) immune response that occurs over days to weeks to years (vs. that of an immediate response). Hypersensitivity Adaptive immune responses typically local inflammation mediated by T-cells or B-cells where antigen presenting cells such as macrophages act as gate keepers. IL-1b Interluekin 1 almost exclusively produced by inflammasome reaction, such as occurs in a macrophage response to implant debris particles.

☆

118 119 119 120 121 121 122 126 126 126 128 128 129 130 130

metal-LTT Metal-lymphocyte transformation test (proliferation assay) used as a human diagnostic test for delayed type hypersensitivity responses to implant metals. Inflammasome Key molecular components of a proinflammatory pathway that reacts to danger signals (not pathogens) that are produced when cells are damaged, typically composed of multiprotein oligomers consisting of caspase 1, PYCARD, NALP and sometimes caspase 5 (also known as caspase 11 or ICH-3).

Change History: October 2016. N.J. Hallab and J.J Jacobs made updates to all sections and updated “Reference” section.

This is an update of N.J. Hallab and J.J. Jacobs, 6.608 – Implant Debris: Clinical Data and Relevance. In Comprehensive Biomaterials, edited by Paul Ducheyne, Elsevier, Oxford, 2011, pp. 97–107.

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Comprehensive Biomaterials II, Volume 7

doi:10.1016/B978-0-12-803581-8.10177-8

Implant Debris: Clinical Data and Relevance

7.8.1

119

Introduction

It is well established that implant debris causes local inflammation, limiting the long term performance of over 1 million total joint arthroplasties implanted each year in the United States.16,17 The costs associated with the failure of these implant is staggering, with approximately $20 billion in the United States per year and is expected to double over the next 10 years.61–63 Not only is this costly in term of health care expenses to the millions of elderly people who may need a revision in their last decades but the incidence of mortality from revision orthopedic surgery can be as high as 13% in people older 475–80 years of age while it is o1% in patients o70 years of age). Not only are eventual implant failures risky mortality wise but they also have high complication rates associated with revised implants, with a 420% chance of post-operative dislocation (vs o1% in patients o75 years of age).84 Some designs of joint replacements release more reactive debris that result in extraordinarily high failure rates, with levels of failure as high as 5% at 6 years post-op, for example, some current metal-on-metal total hip arthroplasties designs as well as some types of highly modular implants (ie, several components that press fit together), that results in metal release from the implants.19,49,59,77 Debris induced inflammation is well known to induce local innate immune responses, ie, monocytes/macrophages activate NFκb and secretion of IL-1b, TNF-a, IL-6 and IL-814,15,37,56,89,95 resulting in localized inflammation.56,64 Over the long term all implant debris this inflammation results in bone loss and loss of implant fixation.106 This phenomenon of bone loss is called “aseptic osteolysis” and results in pain and premature loosening of orthopedic implants.1,2,50 However, aseptic (non-infection related) osteolysis generally only refers to bone loss around an implant that is visible on X-ray, Fig. 1. It is the degradation products of orthopedic biomaterials (generated by wear, and electrochemical corrosion) that mediate this adverse effect. How this debris is produced via fretting corrosion is beyond the scope of this chapter. Debris may be present as particulate wear, colloidal nanometer size complexes (specifically or non-specifically bound by protein), free metallic ions, inorganic metal salts/oxides, or in an organic storage form such as hemosiderin. Particulate debris have extremely large specific surface areas available for interaction with the surroundings for a given mass of debris which can cause or increase chronic elevations in serum metal content from implant degradation. This chapter will focus on biomaterial degradation (through wear and electrochemical corrosion), dissemination of debris, and consequent local/systemic effects. General mechanisms are beyond the scope of this chapter.

7.8.2

Implant Debris Types: Particles and Ions

The debris from of all orthopedic implants can be one of two basic types: particles or soluble debris (metal ions). The difference between particles and ions blurs as the size of particles decreases into the nanometer range and become “soluble.” Typically, particulate wear debris (metal, ceramic or polymers) exists from 40 nm to 1 mm in size, while so called “soluble debris” is limited to metal ions (or nano-particles that are too small to be distinguished from ions) and are bound to plasma proteins.

7.8.2.1

Particulate Debris

Different types of joint arthroplasty produce different amounts of wear debris, and also different sizes and shapes of that are implant and material specific. For instance, hard-on-hard bearing couples such as metal-on-metal hips replacements generally

Fig. 1 Peri-implant aseptic osteolysis above the acetabular cup of a metal-on-polymer bearing total hip replacement. Inset shows a granuloma surrounding acetabular fixation screw, which is a common site for bone resorption due to the ease with which particles can migrate and cause inflammatory soft tissue and osteolysis. Courtesy of BioEngineering Solutions Inc.

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Implant Debris: Clinical Data and Relevance

Fig. 2 Implant debris from metal (Cobalt alloy and Titanium) and ceramic (alumina) debris are more rounded in comparison to polymeric (UHMWPE) debris which is more elongated in shape. Note: Bar¼5 mm. Courtesy of BioEngineering Solutions Inc.

produce smaller sized (sub-micron), fairly round debris whereas traditional metal-on-polymer bearings produce larger (micron sized) debris that is more elongated in shape, Fig. 2. Hard-on-hard material couples (eg, metal-on-metal) also produce smaller debris than do hard-on-soft material couples, (eg, metal on polyethylene). Implants with metal-on-poly bearings are comprised of polymer particles that generally fall into the range from 0.23 to 1 mm, with little metallic debris. Other sources of metal debris include corrosion at metal-to-metal connections between modular components of orthopedic implants where ultra high molecular weight polyethylene (UHMWPE) wear debris in peri-implant tissues, have shown that 70–90% of recovered particulates were submicron, with the mean size being approximately 0.5 mm.11,52,66 Highly cross-linked polyethylene used in current models of hip replacements have demonstrated the production of smaller more rounded debris in the submicron range as small as 0.1 microns in size.13,87 Metal and ceramic bearings produce particles that are generally an order of magnitude smaller than polymeric particles (at approximately o0.05 mm in diameter, ie, in the nanometer range). Histological analysis of peri-implant tissues have identified different types and sizes of particles.18,47,82,83,96,99,100 Stainless Steel: Stainless steel debris has been found as closely packed, plate-like particle aggregates mostly at steel screw-plate junctions. This debris contains particles of chromium compound ranging in size from 0.5 to 5.0 mm.98 Cobalt alloy: Cobalt alloy debris is a chromium-phosphate (Cr(PO4)4H2O) hydrate rich material termed “orthophosphate,” which ranges in size from o1 to 4500 mm.97,98 Titanium Alloy: The degradation products observed in histologic sections of tissues adjacent to titanium base alloys generally have the same elemental composition as the parent alloy, as opposed to corrosion products produced from stainless steel and cobalt–chromium alloys used in implants.

7.8.2.1.1

Particle characterization

Traditionally clinical analysis of particle characterization uses such methods as Scanning Electron Microscopy (SEM) or Transmission Electron Microscopy (TEM), both of which are number-based counting methods. These methods have biased our current understanding and indicated that the majority of the wear (mass loss) from an implant is comprised of particles in the nanometer to submicron range. This stems from the limited number of particles in tissues and the relatively low numbers of particles, (eg, 100–1000s) that are counted using image based analysis techniques such as SEM. While newer analytical techniques, such as low angle laser light scattering (LALLS) analysis have the capability of sampling millions to billions of particles, counted as they pass in front of and scatter a laser light beam proportionally to their size, there is limited ability to use these more comprehensive assessment due to the large amount of debris needed to analyze. As millions of particles flow by a laser in a LALLS analysis the one-in-a-million large particle that equals the mass of the last million small particle can be detected, and thus provide a more accurate accounting of the total debris. The ability to comprehensively characterize implant debris is important to the new designs and bearing surfaces used in new and older implants. A multi-analysis approach is necessary because a given amount of wear debris (weight loss from the implant)

Implant Debris: Clinical Data and Relevance

121

Fig. 3 LALLS analyses of two implant debris samples using a (a) volume and (b) number distributions, demonstrates that similar number distributions and estimates of particle size can result from two very different sizes particles when analyzed using a volume distribution, which shows the size of the particle as a percent of the total volume. Note: The x-axis is particle diameter and the y-axis is (a) percentage of total number of particles in each size range and (b) the percentage of total mass in each size range. Courtesy of BioEngineering Solutions Inc.

after a year of use could be attributed to the loss of a relatively few large particles, or hundreds of millions of small particles (eg, approx 0.2 mm3 volume loss after a million cycles of use could be from approx 400 particles of 100 microns diameter or 400 million particles only 1 micron in diameter). The aforementioned bias of SEM techniques are limited to “number-based” analysis where two very similar number based distributions can look very different when analyzed on a “volume-based” perspective. This is illustrated in Fig. 3 that compared two samples A and B, where very different volume-based distributions are shown to look like very similar number-based distributions. Unfortunately in implant debris analysis of tissues or simulator fluids there is usually o0.05 mg of debris required for obtaining an accurate LALLS volume distribution and thus SEM and TEM analyses remain the standard methods used to characterize debris.

7.8.2.2

Metal Ions (Soluble Debris)

There is continuing clinical concern regarding the release of chemically active metal ions, which bind to proteins and remain in a solution form and then disseminate systemically into surrounding tissues, bloodstream and remote organs. Normal serum levels of implant metals are as follows: 1–10 ng/mL Al, 0.15 ng/mL Cr, o0.01 ng/mL V, 0.1–0.2 ng/mL Co and o4.1 ng/mL Ti. These levels increase following total joint arthroplasty (TJA) (Table 1). Particulate metallic wear debris contributes to this increased metal because of the large surface areas available for electrochemical dissolution.47,96–99

7.8.2.2.1

Metal ion release

Metal release from implants has always been of concern both systemically and locally. Increased levels of serum and urine Co and Cr are detected following even successful total joint replacements (TJRs) of Co-alloy based components. Similarly, increased serum Ti and Cr concentrations are found in subjects with well-functioning Ti and/or Cr containing THR components

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Implant Debris: Clinical Data and Relevance

Table 1

Approximate concentrations of metal in human body fluids and in human tissue with and without total joint replacements21,47,55,76,90

Body fluids (ng/mL or ppb) Serum Normal TJA Urine Normal TJA Synovial fluid Normal TJA Joint capsule Normal TJA-F Whole Blood Normal TJA Body tissues (mg/g) Skeletal muscle Liver Lung Spleen Psuedocapsule Kidney Lymphatic Tissue Heart

Normal TJA Normal TJA Normal TJA Normal TJA Normal TJA Normal TJA Normal TJA Normal TJA

Ti

Al

V

Co

Cr

0.06 0.09 o0.04 0.07 0.27 11.5 15.0 399 0.35 1.4

0.08 0.09 0.24 0.24 4.0 24 35 47 0.48 8.1

o0.02 0.03 0.01 o0.01 0.10 1.2 2.4 29 0.12 0.45

0.003 0.007

0.085 10 0.42 14 0.002 0.33

0.001 0.006 0.001 0.009 0.058 7.4 2.6 64 0.058 2.1

 

 

 

100 560 710 980 70 1280 o65 39,400

890 680 9830 8740 800 1070 120 460

14 22 26 23 o9 12 o9 121

o12 160 120 15,200

o12 570 o14 1130

30 1600 50 5490 30 60 10 390 30 280

10 180 150 3820 o40 o40 690 690 30 90

     

     

     

 

 

 

Mo

Ni

   

 

0.219 0.604 0.177 4.65 0.009 0.104

0.086 0.55 69 100 0.078 0.50

               

               

0.007 o0.16

Normal: Subjects without any metallic prosthesis (not including dental). TJA: Subjects with total joint arthroplasty.  ¼Data Not Available.

(Table 1).21,47,55,75,90 While increases in Ni have been noted immediately following surgery, this increase is likely related to the use of stainless steel surgical instruments or the metabolic changes associated with the surgery itself. Many factors can affect metal ion levels within serum and urine of TJA patients, the most important of which is unintended metal wear. For example, Ti levels up to a hundred times higher than normal have been reported in cases of failed metalbacked patellar components where unintended metal/metal articulation was result of malpositioning of the implant or wearing through of the polymer lining. However in cases of excessive Ti-alloy wear and metal release, there was still no increase in serum or urine Al, serum or urine V levels, or urine Ti levels. The second most important mechanism of metal release is mechanically assisted corrosion, fretting corrosion, of modular implant components that fit together, such as the head and neck junction of stems in total hip arthroplasty (THA), which has been associated with elevations in serum Co and urine Cr.47,53,54 Another source of metal release is in general corrosion which takes place on any surface and increases in proportion the surface area available, where porous coating on implant components give rise to higher serum and urine chromium concentrations due to the larger surface area available for passive dissolution. Where does this metal circulate and accumulate? Homogenates of remote organs and tissue obtained from people with living wills to donate their bodies upon death for research have found significant increases in Co and Cr concentrations occur in the heart, liver, kidney, spleen, and lymphatic tissue (Table 1). But the majority of metal debris remains local to the implant and is most often “kept” with the pseudocapsule that forms around a total joint implant and act much like a joint capsule with pseudo-synovial fluid as well. Increased levels of Ti, Al, and V in joint pseudocapsules have been found with up to 200 ppm of Ti (six orders of magnitude greater than that of controls), 880 ppb of Al, and 250 ppb of V. Other filtering organs such spleen have been associated with increased Al levels and liver has been found to contained increased Ti concentrations in people with failed titanium-alloy implants.46

7.8.2.3

Local Tissue Effects of Wear and Corrosion

Implant debris is the major determinant of long-term performance because local inflammatory responses lead to bone erosion and implant loosening. Normal bone relies on the balance of bone formation and bone resorption forces (bone homeostasis), which involves the coordinated function of osteoblasts (bone building cells) and osteoclasts (bone resorbing cells) and osteocytes (bone

Implant Debris: Clinical Data and Relevance

123

mechanotransduction and signaling network cells). If implant debris induced inflammation causes a decrease in osteoblastic bone formation or an increase in osteoclastic bone resorption, the result will be a net bone loss and osteolysis. This bone loss (ie, osteolysis) around an implant is the primary pathology associated with the local effects of orthopedic implant degradation. This bone loss occurs as a diffuse cortical thinning or as focal cyst-like lesions. Particulate polymethylmethacrylate (PMMA) bone cement and old acetabular cups made of teflon (polytetraflouroethylene) (PTFE) that produced massive amounts of implant debris were the first materials to be associated with osteolytic lesions based on histological studies demonstrating debris associated with macrophages, giant cells and a vascular granulation tissue. It is now known that osteolysis in both loose and well-fixed uncemented implants occurs from particle debris generated from any material.51,103 Goldring et al.27 were among the first to describe that the bone-implant interface in patients with loose total hip replacements is similar to synovial-like membrane and that cells within the membrane have the capacity to produce bone resorbing factors such as PGE2 and collagenase. Particle induced osteolysis is associated less frequently with total knee arthroplasty than with THA. It is unclear why this is. However, factors such as implant/bone mechanical loading environments, differential mechanisms of hip and knee wear, and differences in interfacial barriers to migration of debris have all been postulated to account for this apparent disparity. One unavoidable fact is that all implant debris causes low-grade inflammation that can ultimately lead to implant failure. Exactly how this happens remains somewhat debatable however, increasing evidence by us and others point to the mediation of this inflammation by immune danger signaling which is how the immune system reacts to non-pathogen derived biologic insult.8,10,22,44,78 Over the past 40 years we have learned that implant debris induced inflammation is caused in largely by macrophages which react to implant aseptic (non-infected) debris in a way that results in up-regulating pro-inflammatory transcription factors (eg, NFκb) that produce, amplify and result in the secretion of inflammatory cytokines like IL-1b, TNF-a, IL-6 and IL-8,51 Fig. 4. Prostaglandins, (eg, PGE2), are also involved in debris induced inflammation and osteolysis. Anti-inflammatory cytokines such as IL-10 that modulate this inflammatory process but it remains largely unknown to what degree which ones are important and how to use this to decrease the pathology of particle induced inflammation. Other factors involved with bone loss include the enzymes responsible for catabolism of the organic component of bone, which include matrix metalloproteinases collagenase and stromelysin. Activated immune and bone cells can produce several mediators known to be involved in stimulation osteoclast differentiation and maturation, such as receptor activator of nuclear factor Kappa beta ligand (RANKL) (also referred to as osteoclast differentiation factor). Implant debris is relatively sterile, inert, and does not “look” like a pathogen in any molecularly recognizable way. How then does implant debris provoke an inflammatory response? In other words, how can extra and intracellular mechanisms sense and respond to sterile non-biological material such as implant debris? While this question has remained largely unknown for the past half century years, new discoveries in immunology have implicated the “inflammasome,” danger signaling pathway, Fig. 5.9 The first of these discoveries were pattern recognition receptors (PRRs), which were discovered in 1996, in the membrane and cytosol of human immune cells, such as macrophages. These were defined as toll-like receptors which recognize specific bacterial glycoprotein patterns now called “pathogen associated molecular patterns” or PAMPs. The kinds of identified PAMP receptors now include toll-like receptors (TLRs),92 mannose receptors (MR) and NOD-like receptors (NLRs).67 These pattern recognition receptors (PRRs) initiate events that activate the cell and induce the secretion of pro-inflammatory cytokines leading to a broader inflammatory response. Similarly to PAMPs, non-pathogenic derived stimuli were found to activate immune cells via a novel danger signal pathway. The key molecular components in this pathway were named the “inflammasome” and things that activate it were termed “danger associated molecular patterns,” (DAMPs).69 So now there are pathogen associated molecular patterns (PAMPs) (pathogens) and DAMPs (something the cell recognizes as a danger signal that is or will likely cause cell damage). Thus this new paradigm for immune system activation now includes specific receptors that recognize both PAMPs and DAMPs.71,94 This is important because the inflammasome pathway was the first pathway to explain how cells transduce sterile, non-pathogen derived stimuli (eg, cell stress and cell necrosis) into an inflammatory response.67,68 Other non-biological derived danger signals include such cell damaging stimuli as UV light, particulate adjuvants present in modern vaccines22,44 and, as it turns out, implant debris.8 When particles activate the inflammasome pathway, cells release of IL-1b, IL-18, IL-33 and other cytokines. This happens as follows: Debris-Phagocytosis-Lysosome damage-ROSðreactive oxygen speciesÞ-InflammasomeðNALP3=ASCÞ-Caspase1IL‐1bðand other IL‐1‐familyÞ cytokines That is, once ingested by immune cells particles (or DAMPs, such as asbestos and implant debris, etc.) induce some degree of lysosomal destabilization. This lysosomal destabilization then causes an increase in nicotinamide adenine dinucleotide phosphateoxidase (NADPH), and an associated increase in reactive oxygen species (ROS). This release is comes from the protease and acid rich extreme environment inside lysosomes used to breakdown ingested particles/bacteria, etc. The release of these intracellular ROS species then activate the intracellular multi-protein “inflammasome” complex which is composed of NALP3 (NACHT-, LRR- and pyrin domain-containing protein 3) in association with apoptosis-associated speck-like protein containing a CARD domain (ASC).67,81 This inflammasome activation then activates Caspase-1, which then converts cytokines such as IL-1b and IL-18 (and others) into their active form. So this illustrates the many steps involved in this relatively simple danger signaling pathway and the many new potential places of pharmacologically blocking this response to prevent particle induced inflammation and osteolysis.

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Implant Debris: Clinical Data and Relevance

Fig. 4 Numerous cytokines from peri-implant cells reacting to implant debris can negatively affect bone turnover. IL-1, IL-6, and TNF-a are some of the most potent cytokines responsible for increasing bone loss and enhancing pro-inflammatory responses. Courtesy of BioEngineering Solutions Inc.

Implant Debris: Clinical Data and Relevance

125

Fig. 5 Metal-induced inflammasome activation occurs when soluble and/or particulate implant debris activate the Nalp3 inflammasome when chemicals inside intracellular compartments used to digest foreign material (such as phagosomal NADPH induced ROS and/or Cathepsin B) leaks out of these compartments in an event called phagosomal destabilization. The inflammasome complex, Nalp3-ASC then induces the activation of caspase-1, which in turn allows mature IL-1b to be secreted. IL-1b is a very potent pro-inflammatory cytokine that exerts an autocrine and paracrine effect inducing a broader more potent inflammatory response (eg, activation of NFκb pro-inflammatory responses). Courtesy of BioEngineering Solutions Inc.

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Implant Debris: Clinical Data and Relevance

7.8.2.4

Systemic Effects of Wear and Corrosion

Implant surfaces and wear debris generated are always releasing chemically active metal ions into the surrounding tissues, to some degree. While these metal ions bound to serum proteins may reside in local tissues, they are also transported via the bloodstream and the lymphatics to remote organs. There is concern about this because of the known potential toxicities of the elements used in modern orthopedic implant alloys: titanium, aluminum, vanadium, cobalt, chromium, and nickel. Metal toxicity can occur by altering (1) cell/ tissue metabolism, (2) host/parasite interactions, (3) immunologic interactions and (4) by inducing chemical carcinogenesis.3,5,26,42,65 Cobalt and chromium are essential trace metals required for the normal function of some enzyme reactions. In excessive amounts, however, these elements are toxic. Excessive cobalt can lead to heart problems (cardiomyopathy), excess red blood cells (polycythemia), decreased thyroid functions (hypothyroidism), and carcinogenesis. Excessive chromium has been linked to nephropathy, hypersensitivity and carcinogenesis. Other metals such as nickel can lead to skin rashes (eczematous dermatitis), hypersensitivity reactions and cancer. Excessive vanadium exposure has been linked to heart and kidney dysfunction, and hypertension and depressive psychosis. Aluminum toxicity results in renal failure and blood anemia, bone softening (osteomalacia) and neurological problems. However, it is important to note that theses toxicities generally apply to excessively high levels of the soluble forms of these elements and likely do not apply to the levels of metals released from implant degradation. The association of metal release from orthopedic implants with any associated toxicity is conjectural since cause and effect have not been established, yet. However, discovering any toxicity effects is very difficult given the kinds of problems normally associated with the elderly and thus those expected to occur in any population of orthopedic patients.45

7.8.2.4.1

Systemic particle distribution

What determines the amount of wear debris accumulation in remote organs is not clearly understood. When the magnitude of particulate debris generated by a prosthetic device is increased, there is a corresponding elevation in both the local and systemic burden of particles. Wear particles found systemically beyond the local environment of the implant periprosthetic tissue are primarily in the submicron size range. There have been numerous cases of metallic, ceramic, or polymeric wear debris from hip and knee prostheses in regional and pelvic lymph nodes along with the findings of gross dark staining by metallic debris, fibrosis (buildup of fibrous tissue), lymph node necrosis, and histiocytosis (abnormal function of tissue macrophages). Metallic wear particles have been detected in the para-aortic lymph nodes in up to 70% of patients with TJR components. It is unclear what the ramifications of this is but traditional inflammatory responses to metallic and polymeric debris in lymph nodes includes the same responses seen locally, which are immune activation of macrophages and associated production of cytokines. Thus, lymphatic transport is likely a major route for dissemination of debris where particles migrate via perivascular lymph channels as free or phagocytosed particles within macrophages. Within lymph nodes disseminated particles are mostly submicron in size. However some metallic particles as large as 50 mm and polyethylene particles as large as 30 mm have also been found. These particles can further travel to the liver and spleen where they are found within macrophages or, and in some cases, in nodules of inflammatory tissue granulomas throughout the organs. The size of metallic particles are nearly an order of magnitude less in the liver and spleen, than that in lymph nodes, indicating there is some additional filtration that happens before the particles end up in the those organs. This is not of alarming concern because the cells of liver, spleen, and lymph nodes normally accumulate small amounts of a variety of foreign materials without apparent clinical significance. However, accumulation of excess particles can induce nodules of inflammatory tissue (granulomas) or granulomatoid lesions in the liver and spleen (Fig. 6). The level of reaction to particles in the liver, spleen and lymph nodes is likely modulated, as it is in other tissues by, (1) the number of particles (dose), (2) their rate of accumulation, (3) the duration that they are present and (4) the biologic reactivity of cells to these particles (size and materials composition). It is no surprise that metallic particles in the liver or spleen are more prevalent in subjects with previously failed arthroplasties when compared with cases of well-functioning primary joint replacements. Diseases, which obstruct lymph flow through lymph nodes, such as metastatic tumor, or which cause generalized disturbances of circulation, such as chronic heart disease or diabetes, may be expected to decrease particle migration to remote organs. Other pathologies, such as acute or chronic-active inflammation in the periprosthetic tissues may increase particle migration45,51,104 by recruiting more immune cells to transport the debris away.

7.8.2.4.2

Hypersensitivity

In its broadest definition hypersensitivity to implants is any adaptive immune response typically local inflammation mediated by T-cells or B-cells or macrophages. Thus it is important to note that this response does not need to be excessive to fall into the category of “hypersensitivity response.” When an implant fails prematurely (o7 years) due to an exuberant immune response to a very tolerable amount of implant debris, it is likely that adaptive immune reactivity loosely termed “metal-allergy,” “implantallergy,” or “implant sensitivity,” is central to this reactivity. Released ions, while not sensitizers on their own, can activate the immune system by forming complexes with native proteins. Polymeric wear debris is not easily chemically degraded in vivo and has not been implicated in allergic type immune responses.36,38,38–40 Metals accepted as allergens/sensitizers (haptenic moieties in antigens) include (but are not limited to) the following: beryllium, nickel, cobalt and chromium, tantalum, titanium and vanadium. Nickel is the most common allergen in humans followed by cobalt and chromium. And nickel is still a prominent alloy in medical grade stainless steel Table 2. Generally there are more case reports of hypersensitivity reactions associated with stainless steel and cobalt alloy implants than with titanium alloy components.6,20,23,29,57,72,86,93

Implant Debris: Clinical Data and Relevance

127

Fig. 6 Soft tissue nodules of immune cells and tissue cells called epithelioid granulomas have been found to (a) occur within the portal tract of the liver (  40), and (b) within the splenic parenchyma (  15). (c) The particles within these tissues have been identified as titanium alloy particles using backscattered SEM/EDS analysis of particles in a spleen (  3000). Courtesy of Prof Robert Urban.

Table 2

Approximate weight percent of different metals within popular orthopedic alloys

Alloy Stainless steel (ASTM F138) CoCrMo alloys (ASTM F75) (ASTM F90) (ASTM F562) Ti alloys CPTi (ASTM F67) Ti–6Al–4V (ASTM F136) 45TiNi Zr Alloy (97.5% Zr, 2.5% Nb)

Ni

N

10–15.5 o0.5

Co

Cr

Ti

Mo

Al

Fe

Mn

Cu

W

C

Si



17–19



2–4



61–68



o0.5 o2.0

  

o1.5 o3.0 o1

o1.0 o2.5 o0.15

  



o0.35 o1.0 14–16 o0.15 o1.0   o0.15

  



0.2–0.5



o0.06 o1.0

V



o2.0 9–11 33–37

  

61–66 27–30  46–51 19–20  35 19–21 o1



 

  

  

99 89–91 45

  

5.5–6.5



 

  

  

  

o0.1 o0.08

55

  



  































4.5–7.0 9.0–11

3.5–4.5

Note: Alloy compositions are standardized by the American Society for Testing and Materials (ASTM vol. 13.01). Indicates less than 0.05%.

Dermal and systemic hypersensitivity to metals is common, affecting about 10–15% of the population. Skin contact and ingestion of certain metals result in immune reactions such as eczema (skin hives, redness and itching). Hypersensitivity immune reactions are associated with the adverse performance of metallic cardiovascular, orthopedic and dental implants. Orthopedic implant associated hypersensitivity reactions (metal sensitivity or metal allergy) are generally associated with Type IV Delayed Type Hypersensitivity (DTH), a specific type of cell mediated adaptive immune response. Over the past 20 years growing numbers of case and group studies link immunogenic reactions with adverse performance of metallic cardiovascular, orthopedic and plastic surgical and dental implants, where clinical symptoms have lead directly to device removal. These symptoms include severe dermatitis (inflammation of the skin), urticaria (intensely sensitive and itching red round wheels on the skin), and/or vasculitis (patch inflammation of the walls of small blood vessels). Hypersensitivity (adaptive immune responses) can generally take one of two main forms: (1) an immediate (within minutes) humoral response (initiated by antibody-antigen complexes of types I, II and III reactions), or (2) a delayed (hours to days) cellmediated response.43,60 Implant related hypersensitivity reactions have been well established as type IV DTH. Cell mediated delayed type hypersensitivity is characterized by antigen activation of sensitized T-helper lymphocytes releasing various cytokines, which result in the recruitment and activation of macrophages. These TH cells are characterized by the cytokines they release, including interferon-g (IFN-g), tumor necrosis factor-a (TNF-a), interleukin-1 (IL-1) and interleukin-2 (IL-2). These metal-activated T-cells along with participating antigen presenting cells (APC’s) secrete a variety of cytokines activate other innate immune cells in an autocrine and paracrine manner, ie, macrophages, monocytes, and neutrophils. These cytokines include IL-17, IFN-g and TNF-b which produce a number of effects on local endothelial cells facilitating infiltration; and migration inhibitory

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factor (MIF). In a DTH response there is infiltration, activation and eventual migration inhibition of immune cells away from the site of inflammation. Attracted and activated macrophages have the increased ability to react to and phagocytose, process and present metal-protein complexes in class II MHC complexes and release inflammatory mediators such as IL-1, a strong proinflammatory danger signaling cytokine which all together triggers the activation of more T cells, which in turn activates more macrophages, which activate more T-cells, in a vicious cycle. If left unchecked this DTH vicious cycle response can create extensive tissue damage. Current research efforts to use immunosuppressive therapy in people to temporarily stop this cycle are currently underway. 7.8.2.4.2.1 Incidence of hypersensitivity responses among patients with metal implants The incidence of metal sensitivity among people with well-functioning implants is about twice as high as that of the general population, approximately 25% (vs. 10%, Fig. 7). Moreover, the incidence of metal sensitivity among people with a “failing” implant (in need of revision surgery) or with a well-performing metal-on-metal articulating implant is approximately 50–60% (Fig. 7). This increased prevalence of metal sensitivity among people with a failing metal-on-polymer prosthesis has prompted the speculation that immunological processes may be a factor in implant loosening. Cohort studies over the past 30 þ years have generally indicated a correlation between metal implants and metal sensitivity,36 clearly indicating that metal sensitivity can be a contributing factor to implant failure74,85,86 (Fig. 7). Thus metal allergy testing (“metal-LTT”) may be warranted for people with a history of metal allergy prior to receiving an implant. The importance of this line of investigation is growing, as the use of metallic spinal implants is increasing and as expectations of implant durability and performance increase.4,48 7.8.2.4.2.2 Testing for metal sensitivity Implant debris related DTH responses are bad enough to require revision arthroplasty in approximately 1–2% of all orthopedic patients. There are only two accepted testing methods for diagnosing metal allergy includes skin testing (ie, so-called patch testing) and cell culture blood testing called metal lymphocyte transformation testing (metal-LTT). Patch testing commercial kits exist for some metals,43,85 however there is continuing concern about sensitizing patients using this type of patch testing (by placing high concentration metal salt solutions in petrolatum jelly on the skin for 48 h).73 Other problems associated with patch testing is disagreement as to how representative is the skin (with unique dermal antigen presenting cells, ie, Langerhans cells) as a proxy of peri-implant antigen presenting cells.58,60 In vitro metal allergy testing, called lymphocyte proliferation testing (also known as LTT), involves measuring the proliferative response of lymphocytes after they are activated by an antigen. A radioactive marker is used to precisely measure the amount of cell division over a set time period by measuring the amount of radioactive [H3]thymidine that is incorporated into the cellular DNA upon cell division after 4–6 days of exposure to antigen. [3H]-thymidine

Fig. 7 A compilation of investigations showing the averaged percentage of metal sensitivity among the general population, people with wellfunctioning implants, people with metal-on-metal implants and people with failing implants (prior to getting them revised). Metal incidence rates include a positive response to allergy testing for nickel, cobalt and/or chromium. All subjects were tested by means of a patch or metal lymphocyte transformation test (LTT). Courtesy of Orthopedic Analysis LLC.

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uptake is measured using liquid scintillation, and the amount of immune response (proliferation factor or stimulation index) is calculated using measured radiation counts per minute (cpm): Proliferation Factor ¼ ðcpm with treatmentÞ=ðcpm without treatmentÞ The use of proliferation testing to measure metal allergy was developed from similar methods to assess general drug sensitivity and has been well established as a method of testing DTH responses in a variety of clinical settings.24,88,91,101,102 The use of LTT for implant-related metal sensitivity is increasing given that it has been shown to have diagnostic efficacy particularly in the area of metal-on-metal implants, which have led to higher rates of metal sensitivity responses.12,32,35 Several investigations indicate that metal allergy can be more readily detected by LTT than by dermal patch testing.12,30,34 Thus, given the growing number of studies using the highly quantitative nature of LTT testing in orthopedics it is likely better suited for the testing of implant-related sensitivity than dermal patch testing.12,24,31,33,88,91,101,102 As we learn more about the subtleties of immune response to implant debris, the adaptive immune system may be involved to a much larger degree in debris induced inflammation than what has been previously attributed to the innate immune system via macrophages reactivity.

7.8.2.4.3

Carcinogenesis

The carcinogenic potential of implant debris remains an area of concern. Animal studies have documented that implant metals can act as carcinogens. Small increases in rat sarcomas were found to correlate with high levels of serum cobalt, chromium, or nickel content produced by metal implants. Additionally, lymphomas with some form of bone involvement were also more commonly found in rat animal models with metallic implants. Although not common, implant site tumors in dogs and cats – primarily osteosarcoma and fibrosarcoma have been associated with stainless steel internal fixation devices. Some epidemiological studies implicate orthopedic implants in causing cancer 10–20 years after total hip replacement. However, more recently larger studies have found no significant increase in cancers such as leukemia or lymphoma, although these studies did not include people with high amounts of metal such as those with a metal-on-metal prosthesis. The many differences in the populations with and without implants that do not depend on the implant itself confounds the interpretation of any epidemiological investigations. It remains unknown if metal release from orthopedic implants is carcinogenic because causality has not been established in human subjects, and in fact testing by the authors found that peri-implant cells became toxic prior to any DNA strand breaks when tested with increasing concentrations of metal ions found in implants.7,41 The actual number of cases of tumors associated with orthopedic implants is likely under reported due to the frequency of tumors in the population demographic receiving metal implants. However, compared to the number of devices implanted on a yearly basis (over 1 million) the incidence of cancer at the site of implantation is relatively rare. Continued monitoring and large long epidemiological studies are required to fully understand this risk.25,70,79,105

Fig. 8 A number of factors can tip the scales away from bone homeostasis and toward net bone loss. Particle induced inflammation is one of these factors and induces the release of potent cellular messages (inflammatory cytokines) which causes bone depositing cells called osteoblasts to stop producing bone and causes bone resorbing cells call osteoclasts to start increasing resorption. Over time, this results in a net bone loss and loosening of implants.

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7.8.3

Conclusions

Total joint implants are a miracle of modern medicine, returning mobility, independence and quality of life to millions every year. Implant debris is unavoidable and results in activation of the innate immune system resulting in local inflammation that over time causes more bone loss then homeostatic mechanisms can keep up with, and the result is implant loosening, via aseptic osteolysis (Fig. 8). When this reactivity is excessive it may activate the adaptive immune systems and results in allergic type response involving T-cells. Newer kinds of “alternative” bearings used in total joint implants such as metal-on-metal articulating components have resulted in new types of biologic responses including lymphocyte dominated granuloma-like lesions in to bone (termed ALVAL, for aseptic lymphocyte vasculitis associated lesion), found around some implants. This type of response seem to encompass features of innate and adaptive immune responses,28,80 and demonstrates that that both innate (macrophage) and adaptive (T lymphocyte) immune system reactivity can act to limit the lifetime of current TJR implants. Advances at the molecular and cellular level increase our understanding of inflammatory bone loss. Treatment options ranging from diagnosing pre-existing conditions of metal allergy (metal-LTT), general management of inflammation (eg, NSAIDS) to selective blocking of cellular mediators (eg, anti-IL-6, anti-TNF-a, IL-1b-receptor antagonist, etc.) are all part of the modern arsenal used to help fight the problem of implant debris induced inflammatory bone loss. There is increasing need for clinical studies to define the role of metal allergy, genetic susceptibility to particle-induced inflammation, general biologic variability, and prosthesis-related factors in the pathogenesis of non-specific and specific biologic responses to implant debris.

See also: 7.6 Biological Effects of Wear Debris From Joint Arthroplasties. 7.7 Fretting Corrosion of Orthopedic Implants

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