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The pathology of joint replacement and tissue engineering
Anthony Freemont
Anthony Freemont BSc MD FRCP FRCPath is Professor of Osteoarticular
Pathology in the Faculty of Biology, Medicine and Health, University of
Manchester,
UK. Conflicts of interest: none declared.
Abstract
Joint replacement is very common and undertaken in most hospitals in one
form or another. Tissue engineering of connective tissues generally, and joints
in particular, is becoming more common. With increased usage, these
techniques generate iatrogenic morbidity. The diagnosis and exclusion of
iatrogenic disease is an increasingly important area of pathologists’ working
lives. This article discusses the disorders that can arise in association with joint
replacement and tissue engineering of joints and describes a relatively new
disease (Adverse Reaction to Metal Debris [ARMD]) the first of what may
become many new disorders associated with the new therapeutics covered in
this article.
Keywords infection; joint replacement; osteoarticular; pathology; tissue
engineering
Background
The pioneering research of John Charnley is generally considered to have
triggered the revolution that led to modern joint replacement surgery.1
1
Charnley’s work laid the practical foundations for the use of inorganic
engineered materials, such as metals and plastics, to restore joint function by
replacing malfunctioning articular surfaces. These new techniques were not
without their problems. More recently two new branches of connective tissue
medicine, tissue engineering and regenerative medicine, have focused minds
on the possibility of replacing damaged tissue with new.
As with all medical innovations, problems are recognized that with time
change the practice of pathology. The problems associated with the pathology
of joint tissue replacement and regeneration can be considered under four
headings:
Replacement of articular surfaces
Replacement of non-articulating intra-articular structures
Intra-articular injectable agents
Tissue engineering/regeneration
Replacement of articular surfaces
Background
The purpose of joint replacement (arthroplasty) is to improve the limited
movement and reduce pain caused by damage to articular surfaces. This is
achieved by either replacing diseased articulating surfaces with artificial ones
(e.g. hip replacements) or by replacing the entire joint with a prosthesis (e.g.
finger joints).
Artificial articulating surfaces are usually constructed of metals, plastics or
ceramics, or combinations of these materials. Some are used solely for
resurfacing the joint, whilst others replace the articulating surfaces and
2
adjacent bone. Often they are held in place using cements consisting most
commonly of acrylic resins. Recently there has been a trend towards coating
the stems of implants with materials such as hydroxyapatite that are said to
promote bone growth into the prosthesis, with the hope of preventing
loosening, a problem that requires revision and a new prosthesis.
Typically, both sides of a joint wear out together and arthroplasty surgery
replaces both articular surfaces. If this is the case, the two opposing prosthetic
surfaces may consist of the same or different materials. Traditionally the
articulations were metal on plastic. They are highly successful but in a
proportion of patients the differences in physical properties of the two
surfaces leads to wear and formation of significant numbers of wear particles,
which initiate a macrophage and giant cell reaction leading to bone loss and
implant loosening. Advances in materials design has resulted in manufacture of
articulations with reduced wear particle production. Of these the combination
of metal articulating on crosslinked polyethylene (PE), metal on metal, and
ceramic-on-ceramic articulations have all demonstrated lower rates of in vivo
wear particle generation than the original metal-on-plastic ones.
The properties of wear particles derived from inorganic materials used in
joint replacement
Cross-linked polyethylene: ultrahigh molecular weight polyethylene
(UHMWPE) is the most commonly used material for acetabular and tibial
prostheses.2 It has good biocompatibility but it does undergo wear. The wear
particles vary in size from a few to several hundred micrometres long. The
particles are intensely birefringent and remain in tissue after conventional
processing (Figure 1a).
3
Metals: the most common metals used for articulations are low carbon
stainless steels and cobalt-chrome. Metals may be scratched, particularly
during implantation, which initiates wear.
Many stems of knee and hip implants are made of alloys of titanium, vanadium
and aluminium. This material can also wear. There is evidence that titanium
can preferentially elute from the alloy. Although inert, titanium can
disseminate widely throughout the body.3
Metal wear particles show up as tiny dark flecks, usually within macrophages in
tissue sections of synovium (Figure 1b) or the soft tissue membranes that
develop between implants and surrounding bone.
Ceramics: these (e.g. alumina [Al2O3]) are harder than the equivalent metals
and can produce very smooth surfaces that are extremely unlikely to wear.
They are, however, more brittle and more likely to fracture (in practice this
occurs in <1:400 cases). The fragments produced by wear and fracture have no
specific features, being a granular material that resembles hydroxyapatite.4
Cement: most commonly cements are acrylic resins, such as
polymethylmethacrylate (PMMA). PMMA forms by hyperthermic
polymerization of a liquid monomer. During polymerization the cement sticks
to the implant’s stem and, because it is introduced into the marrow as a liquid
that can permeate between bone trabeculae, when it polymerizes, it binds
itself into the trabecular network, fixing the prosthesis tightly to the adjacent
bone. The cement is doped with particles of metal such as barium to render
the cement radiodense. Under the microscope cement appears as a large,
clear, rounded nodule surrounded by macrophages and multinucleate giant
cells and containing dark refractile rounded granules of the doping metal
(Figure 1c).
4
Hinge materials: some small joints (eg. Finger joints) are replaced by plastic
hinges. The hinge materials are usually made from the silicone-based polymer,
silastic. With frequent use silastic may break, releasing particulate material
which can spread to other areas of the body via the lymphatics. This material is
refractile, granular and usually intracellular within macrophages or
synoviocytes (Figure 1d).
Complications of joint replacement surgery
Arthroplasty is a very successful procedure, however, there is a 10 year failure
rate of about 2%, the major causes of which are:
Dislocation. This is a complication that is related to the success of the
surgical procedure itself and the laxity of supporting tissues.
Damage to the prosthesis. With modern materials these events are
rare.5
Aseptic loosening
Infection. This is relatively uncommon, important and dealt with later.
Aseptic loosening
Background: aseptic loosening is the most common complication of joint
replacement surgery accounting for between half and three quarters of all
revisions. It is often associated with periprosthetic bone loss/osteolysis, which
may be rapid and make revision surgery difficult.
The majority of prostheses are attached to a stem that is pushed into the shaft
of the bone. Around the stem is a potential space in continuity with the joint
cavity. This space is often filled by cement and/or host fibrous tissue and bone.
Under load an imperfectly fixed stem may work loose opening a gap between
the implant into which wear particles generated inside the joint can be forced.
5
Here they initiate a macrophage and osteoclast reaction that leads to bone loss
and loosening.
Of the potential wear particles polyethylene is the most bioactive. The particles
vary in size but the submicron particles induce a greater inflammatory
response in vitro than do larger particles.6 The cellular response is also
dependent on the number and shape of the particles; elongated particles
generating a more severe inflammatory reaction than globular ones.7
Metal wear particles are smaller than those from polyethylene. Despite their
size, they may be so numerous that they stain the capsule black (“metallosis”).
In histological sections metal particles are usually seen within macrophages of
synovium and pseudomembranes around prosthetic stems. They may be
associated with necrosis. Particles of metal may also migrate through the bone
marrow and be found in regional lymph nodes. In the synovial fluid they can
cause direct (third body) wear of the surface of implants.
Ceramic materials tend to have better biocompatibility than metal alloys8 but
the size, shape, number, distribution and reactivity of the respective wear
particles has not been fully determined. This said they seem to be less
inflammogenic than either metal or plastic particles. As a generalization,
ceramic wear particles are granular and non-birefringent measuring 0.5-20 μm
in diameter. Like metal particles they can form aggregates. They tend to be
found in macrophages but can elicit a foreign body giant cell response. They
are also found extracellularly, where they appear brown in colour, but lack the
refractility of haemosiderin deposits.
In addition to wear particles from articular surfaces, particles of cement may
enter the synovial fluid and joint tissues. Polymethylmethacrylate (PMMA) is
brittle and particles and fragments of diameter 30-100 μm break off under load
6
forming debris with properties similar to those of surface wear debris. PMMA
itself is dissolved during tissue processing and under the microscope holes
formed from ghosts of dissolved PMMA fragments can be seen containing dark
metal particles. Because of their relatively large size the PMMA particles
initiate a foreign body-type giant cell reaction.
Silastic wear particles are 10-100 μm in size. They are crenulated and
birefringent, usually eliciting a brisk macrophage and multinucleated giant cell
reaction. They can cause osteolysis, painful synovitis, and lymphadenopathy in
regional lymph nodes.9
Wear particles, either following phagocytosis or by activation of cell
surfaces, can change the function of different cell types (particularly
macrophages, fibroblasts, osteoblasts and osteoclasts) within the
bone/marrow around the stem of the prosthesis. 10 Macrophages activated by
phagocytosing wear particles in the synovium and pseudomembrane produce
numerous cytokines, growth factors, chemokines and other mediators (notably
IL-1ß, IL-6, M-CSF, nitric oxide, metalloproteinases)11 that stimulate changes in
local cell and matrix biology. In particular they can give rise to a painful
inflammatory synovitis and osteoclast-mediated periprosthetic osteolysis and
loosening. The osteolysis may be worsened by direct inhibition of osteoblastic
activity by the wear particles themselves, particularly metal particles.
In addition to osteolysis being mediated by a foreign bodytype response to
wear particles, in some patients the presence of a granulomatous response
suggests a type IV hypersensitivity reaction.
Pathological findings: in patients with a painful joint replacement the clinician
is usually seeking guidance on the causes of pain and/or swelling. In particular
7
(s)he is asking the pathologist to exclude infection or ARMD (see below). One
or more of three tissues is/are commonly sampled:
Synovium
Pseudomembrane
Synovial fluid
Synovium - After the joint capsule is closed around an implant, a crude
synovium forms to line the new joint space. The new synovium has the same
functions and is prone to the same disease processes as synovium anywhere.
Wear particle debris enters the synovium eliciting a macrophage/giant cell
response. The macrophages are often numerous with diffuse brown coloured
cytoplasm, or contain distinct metal/plastic/cement particles. The synovial
subintima is often fibrotic, the synovial surface may become replaced by
granulation tissue, and necrosis may be present. Only rarely is there a
significant lymphocytic infiltrate and polymorphs should not feature unless
infection is present. Necrosis associated with macrophages and giant cells may
be confused with necrotizing granulomatous inflammation especially in small
biopsies. In this setting the recognition of particulate material using direct
vision, polarizing microscopy or special stains (e.g. Oil Red O for polythene)
then becomes paramount.
Although usually carried out for osteoarthritis, joint replacement is sometimes
undertaken as part of the management of inflammatory arthropathies,
particularly rheumatoid arthritis. In this setting the “new” synovium can take
on an identical appearance to that seen in the primary disease.
Pseudomembrane -the pseudomembrane between a loosening implant and
native bone shows the same fibrosis, focal necrosis and macrophage and giant
cell response to that seen in the synovium. The surface of the
8
pseudomembrane abutting the implant may even develop a synoviocyte-like
layer of palisaded “synoviocytes”.11
Synovial fluid - the synovial fluid in joints with implants is usually non-
inflammatory (i.e viscid and with a cell count of <500 cells/mm3). The presence
of >1700 cells/mm3 should alert one to the possibility of infection (see below).
Wear debris, haemosiderin and macrophages are present in the fluid. The
presence of wear debris indicates wear and not necessarily loosening. Indeed
there is no cytological test for diagnosing loosening.
Special pathology of metal-on-metal articulations Adverse Reaction to Metal
Debris (ARMD)
Background: As a major problem with joint prostheses is loosening of the
stem, attempts have been made to design “stemless” prostheses. As the
earliest and still most frequent joint replacement, loosening of femoral
stemmed prostheses has become a common problem, not because the
technique is flawed but simply because of the huge numbers of procedures
being performed. The problem is particularly serious in the elderly in whom
bone loss through osteoporosis makes revision difficult.
Resurfacing of the damaged articular surface of the femoral head seemed a
perfect solution as it leaves the femoral shaft unaffected should a revision to a
stemmed prosthesis be necessary. Over the past 15 years cobalt-chrome has
become the material of choice both for the femoral head and also the
acetabulum, creating a metal-on-metal articulation. These work extremely
well, however in the last 10 years a complication (ARMD) has become apparent
in a proportion of patients that has been shown to manifest in a number of
different ways.
Pathology: The pathology of ARMD is characterized by (Figure 2a):
9
The formation of pseudotumours; para-articular, often cystic, swellings
that involve fat, fibrous tissue ad muscle
Very extensive tissue necrosis of the synovium and subintima, which
may be very extensive and extend into and through the joint capsule
into surrounding tissues.
Prominent lymphoid cell (usually lymphocyte but occasionally plasma
cell) aggregates in fibrous tissue often, but not exclusively, deep to areas
of necrosis 12. This was originally called “aseptic lymphocytic vasculitis-
associated lesion” or ALVAL. There is no vasculitis.
A band of macrophages within the necrotic tissue. The macrophages
sometimes contain obvious metal particles but in a significant
proportion of cases they do not, instead having a brown tinge to the
cytoplasm or appearing “foamy”. In places macrophages show evidence
of cytotoxicity with histologically detectable cell membrane damage.
Pathogenesis: These patients often have raised levels of cobalt and chromium
in their blood and synoval fluid and these are believed to be the clue to the
pathogenesis of this disorder. It is now accepted that the probable mechanism
of necrosis and ALVAL is stimulation of the adaptive immune response by the
presence of nano-sized wear particles of cobalt and/or chrome. Metallosis as
one of the manifestation of ARMD, is caused by accumulation of larger metal
particles but may also be accompanied by necrosis and ALVAL.
In a recent review 13 Athanasou discusses all the elements of aseptic loosening
and in particular discusses the singular pathology of metal on metal hip
prostheses.
Similar features may be seen in non-metal on metal articulating prostheses
with modular cobalt chrome stems where it has been postulated that the
10
driver of the pathological changes is believed to be wear at the interface
between the modular elements.
Infection
Background: As in all surgery there is a risk of introducing infection at
arthroplasty. The infection rate varies from 1% to 5%. The incidence rises in
revision arthroplasty and in patients with compromized immune systems such
as those with rheumatoid arthritis or diabetes. Factors such as the
characteristics of the operating theatre, the quality of the host bone and soft
tissue, and the complexity and length of the operation all contribute to the
infection risk. Prosthetic material/particulate debris contributes to infection
because bacteria, particularly Staphylococcus epidermidis, readily bind to most
arthroplasty materials. The ability of many bacteria to remain attached to a
surface is enhanced by their production of a biofilm consisting of saccharides,
proteins and nucleic acids. Once established, biofilms attract other bacteria
with less specific adhesion properties to the prosthetic surface, thus forming a
colony of mixed bacterial species.
Frank septic arthritis is rare following arthroplasty, but the presence of the
biofilm encourages low grade, insidious infection which nonetheless leads to
implant loosening indistinguishable from that caused by aseptic loosening. This
condition of periprosthetic infection is also known as septic loosening. It is
particularly poorly responsive to systemic and local antibiotic treatment.
Failure to recognize that osteolysis is infection-related can have disastrous
results if the patient undergoes revision arthroplasty into an infected bone, the
new implant rapidly failing.
If infection is suspected or proven concerted action can eradicate the infection.
High dose long-term antibiotics can be successful, but once loosening has
11
started antibiotic treatment is inneffective and a two stage revision is
undertaken in which the infected implant is removed and replaced with a
cement spacer doped with antibiotic. Usually this is coupled with prolonged
oral antibiotic therapy and only once biomarkers of infection have returned to
normal is the revision completed.
Diagnosis of septic loosening has therefore become a diagnostic priority.
Diagnosing the infected prosthesis: When there is acute septic arthritis or
acute osteomyelitis associated with an arthroplasty, the diagnosis is relatively
straightforward, as there is necrosis and large numbers of polymorphs within
the tissue; together with a high nucleated cell count and high proportion of
polymorphs in the synovial fluid. The causal agent is usually a Gram positive
coccus which is identified by Gram staining or culture.
Low grade infection of the type that leads to periprosthetic infection, is much
more difficult to diagnose, the key feature being the presence of polymorphs
which are never a significant component of inflammatory infiltrates in aseptic
loosening or ARMD.
In most cases, the diagnosis of an infected total joint replacement depends on
a combination of clinical features, radiographic findings, and laboratory test
results, but in the low grade infections that characterize periprosthetic
infection, laboratory techniques are key. A peripheral blood leukocytosis,
raised ESR and CRP might suggest infection, but these tests have
poorsensitivity and specificity, and imaging adds little, nor does culture of
synovial fluid or joint tissue. In this setting tissue biopsy and synovial fluid
analysis prove to be pivotal.
Tissue biopsy: there are a number of studies that have shown the diagnostic
and prognostic significance of identification of polymorphs in the superficial
12
synovium. Arguably the most significant of these was in 1995 when Athanasou
and colleagues in Oxford14 showed that an average of one or more neutrophil
polymorphs per high powered microscope field across a frozen section of
synovium taken intraoperatively gave a diagnostic sensitivity for low grade
infection of 90% and specificity of 96%.
Using the criterion of five polymorphs per high powered field in at least five
fields as evidence of active infection within periprosthetic tissue from the
bone-cement interface or the pseudocapsule, Feldman et al15 achieved a
sensitivity of 100% and a specificity of 96%. As a rule of thumb, >10
polymorphs per high powered field (Figure 2b) over five fields is predictive of
infection, whilst 5-9 is suspicious and <5 has no diagnostic significance. Even
though the organism causing infection is most commonly a Staphylococcus,
Gram staining intra-operative smears or later on tissue sections has a very low
diagnostic yield and adds very little, if anything, to the overall diagnostic
process.
Although lacking the immediacy of intra-operative frozen sections the same
criteria can used for diagnosing infection in conventionally processed tissue,
thus pre-operative open, arthroscopic or blind needle biopsy of synovium can
be used for planning definitive surgery.
Synovial fluid: Synovial fluid analysis has recently been shown to be a useful
investigation in the diagnosis of low grade, periprosthetic infection, and one
that can be used before surgery, allowing planned revision.16 In a prospective
study a synovial fluid leukocyte count >1700/mm3 had a sensitivity of 94% and
specificity of 88% for diagnosing prosthetic joint infection; and if neutrophils
accounted for >65% of the nucleated cells the sensitivity and specificity rose to
97% and 98% respectively.
13
In terms of assessing infection prior to revision for knee arthroplasty this
positions synovial fluid analysis at the forefront of diagnostic tests.
Replacement of intra-articular structures other than articulating surfaces
Attempts have been made to replace intra-articular ligaments such as the
cruciate ligaments and fibrocartilagenous structures such as menisci with
inorganic materials.
Cruciate ligament replacement are usually constructed of loosely twisted or
braided fibrillary materials including plastics, carbon fibre and even
polymerized naturally occurring molecules such as lactic acid. The articifical
ligament has innate strength but the hoped for ingrowth of fibroblasts and
replacement by organized fibroelastic tissue is rarely achieved and the
presence of a macrophage and giant cell response to degrading biomaterial is
the norm.
The synovial fluid in such cases is invariably of low cell count, but fragments of
fibrillar prosthetic material might be seen.
Intra-articular injectable agents
Intra-articular injection is frequently used for delivering therapy into diseased
joints. Examples include steroids and hyaluronans therapeutically and local
anaesthetics prior to arthroscopic surgery.
Steroids
Steroids used to treat inflammation and pain, are usually injected as relatively
insoluble, crystalline preparations which dissolve slowly to give a longer lasting
effect. The carrier medium can very rarely induce a hypersensitivity reaction
with eosinophils and mast cells in the synovial fluid. The steroid crystaloids
14
which can remain in the joint for several weeks, can be mistaken for
pathogenic crystals on subsequent synovial fluid examination. Steroids reduce
inflammation within the synovium and the number of polymorphs within the
synovial fluid.
Hyaluronans
Hyaluronans are being used increasingly for treating noninflammatory
arthropathies, such as trauma and osteoarthritis. They have some beneficial
effects through: decreasing pain nerve sensitivity; enhancing chondrocytic
proteoglycan synthesis; and reducing effects of proinflammatory mediators
and matrix metalloproteinases.
Rarely, patients develop an acute or subacute reaction with pain and swelling
of the joint, which usually settles spontaneously within a day or two. Synovial
fluid samples aspirated at the time have cell counts of 2000-100,000
cells/mm3. This acute reaction can mimic septic arthritis.
A second uncommon reaction has been noted recently in which aggregates of
hyaluronans are absorbed into the synovium where they induce a
granulomatous reaction. In H&E stained sections they appear as naked
granulomata with a central grey amorphous centre surrounded by
mononuclear and multinucleate macrophages 17 (Figure 3a).
Local anaesthetic agents
It is common practice to perform arthroscopies under a form of local
anaesthesia in which a local anaesthetic agent is instilled into the joint. There is
no pathology associated with this as such but some recent evidence has
emerged implicating some local anaesthetic agents in chondrotoxicity. The
significance, if any, of this in Man is unknown.18
15
Tissue engineering/regeneration
Background
Connective tissues have been the focus of much basic and translational tissue
engineering and regenerative medicine research. The major area that has
impacted on the pathologist relates to cartilage replacement/regeneration.
Cartilage resurfacing
The ability of articular cartilage to heal spontaneously is limited, and injury
predisposes to osteoarthritis. Whilst joint replacement is very successful in
relieving symptoms, the life of an implant may be short and revision has a
relatively high morbidity, with the revised implant having, on average, a
shorter life than the original. This is particularly the case in young implant
recipients which increases the reluctance of surgeons to perform joint
replacement surgery in the young and middle aged.
One answer is joint resurfacing with inorganic materials such as metals,
another is to restore the cartilage. In young people the initial, often trauma
induced, damage to cartilage is a relatively small, focal defect. A variety of
techniques have been tried to promote repair by stimulating natural stem cells
most of which involve damaging the subchondral bone and exposing marrow
in the floor of the defect. The mesenchymal stem cells within the marrow are
stimulated to form new bone and cartilaginous tissues within the defect. This
results in the formation of a repair tissue that whilst it may consist in large part
of fibrocartilage which, whilst lacking many of the physical properties of
articular cartilage, successfully achieves the primary goals of pain relief and
delay in the onset of osteoarthritis.
Attempts have also been made to implant tissue engineered cartilage grown
outside the body, but biointegration of such a construct is a real problem.
16
In vivo tissue engineering has been attempted with rather more success. About
30 years ago successful in vivo engineering of cartilage from autologous
chondrocytes (autologous chondrocyte implantation - ACI) was reported.19
The initial approach to ACI involved expanding a population of chondrocytes
harvested from relatively normal but non-weight bearing cartilage in the
affected joint in a laboratory. After population expansion, the cells are placed
in a debrided defect in the cartilage and held in place by sowing a sheet of
material (often periosteum) across the top of the defect.20 At subsequent
arthroscopy, the regenerating tissue has a rigid, elastic consistency and
sometimes grows over the surrounding cartilage. Histologically it usually has
the appearance of fibrocartilage, but sometimes true hyaline cartilage forms.
This has gained relatively wide usage and more recently similar effects have
been documented using autologous mesenchymal stem cells.
The technique cannot be used on large or convex defects. In these settings
cylinders of autologous bone and cartilage have been transplanted into sites of
cartilage loss either to initiate repair or to act as a scaffold for ACI.
Most recently hybrid technologies involving combining damaging subchondral
bone with the use of autologous chondrocytes or mesenchymal stem cells in
biomaterials (mainly gels such as alginate and chitosan), and transplanted
osteochondral cylinders have been trialled. Both autologous cell and tissue
transplantation in all these settings have proved successful in forming cartilage.
The histopathologist is occasionally asked to assess the quality of
biointegration (Figure 3b), particularly at the interface with native cartilage.
Metachromatic stains often delineate engineered cartilage from host cartilage
and the junction can also be identified using polarizing microscopy, the
organization and birefringence of the newly formed cartilage/fibrocartilage
being different from that of the host cartilage. Assessment of the extent of
17
biointegration has clinical value as poor biointegration increases the chances of
failure of the engineered cartilage.
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2. Kurtz SM, Muratoglu OK, Evans M, Edidin AA. Advances in the processing, sterilization, and crosslinking of ultra-high molecular weight polyethylene or total joint arthroplasty. Biomaterials 1999; 20: 1659-88.
3. Urban RM, Jacobs JJ, Tomlinson MJ, Gavrilovic J, Black J, Peoc’h M. Dissemination of wear particles to the liver, spleen, and abdominal lymph nodes of patients with hip or knee replacement. J Bone Joint Surg Am 2000; 82: 457-76.
4. Hannouche D, Hamadouche M, Nizard R, Bizot P, Meunier A, Sedel L. Ceramics in total hip replacement. Clin Orthop Relat Res 2005; 430: 62-71.
5. Schmalzried TP, Shepherd EF, Dorey FJ, et al. The John Charnley Award. Wear is a function of use, not time. Clin Orthop Relat Res. 2000; 381: 36-46.
6. Jacobs JJ, Hallab NJ, Urban RM, Wimmer MA. Wear particles. J Bone Joint Surg Am 2006; 88(suppl 2): 99-102.
7. Yang SY, Ren W, Park Y, et al. Diverse cellular and apoptotic responses to variant shapes of UHMWPE particles in a murine model of inflammation. Biomaterials 2002; 23: 3535-43.
8. Campbell P, Shen FW, McKellop H. Biologic and tribologic considerations of alternative bearing surfaces. Clin Orthop Relat Res 2004;418: 98-111.
9. Yamashina M, Moatamed F. Peri-articular reactions to microscopic erosion of silicone-polymer implants. Light and scanning electron microscopic studies with energy-dispersive X-ray analysis. Am J Surg Pathol 1985; 9: 215-9.
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10. Purdue PE, Koulouvaris P, Potter HG, Nestor BJ, Sculco TP. The cellular and molecular biology of periprosthetic osteolysis. Clin Orthop Relat Res 2007; 454: 251-61.
11. Athanasou NA. The pathology of joint replacement. Curr Diagn Pathol 2002; 8: 26-32.
12. Davies AP, Willert HG, Campbell PA, Learmonth ID, Case CP. An unusual lymphocytic perivascular infiltration in tissues around contemporary metal-on-metal joint replacements. J Bone Joint Surg Am 2005; 87: 18-27.
13. Athanasou NA The pathobiology and pathology of aseptic implant failure.Bone Joint Res. 2016;5:162-8.
14. Athanasou NA, Pandey R, de Steiger R, Crook D, Smith PM. Diagnosis of infection by frozen section during revision arthroplasty. J Bone Joint Surg Br 1995; 77: 28-33.
15. Feldman DS, Lonner JH, Desai P, Zuckerman JD. The role of intraoperative frozen sections in revision total joint arthroplasty. J Bone Joint Surg Am 1995; 77: 1807-13.
16. Trampuz A, Hanssen AD, Osmon DR, Mandrekar J, Steckelberg JM, Patel R. Synovial fluid leukocyte count and differential for the diagnosis of prosthetic knee infection. Am J Med 2004; 117: 556-62.
17. Michou L, Job-Deslandre C, de Pinieux G, Kahan A. Granulomatous synovitis after intraarticular Hylan GF-20. A report of two cases. Joint Bone Spine 2004; 71: 438-40.
18. Piper SL, Kim HT. Comparison of ropivacaine and bupivacaine toxicity in human articular chondrocytes. J Bone Joint Surg Am 2008; 90: 986-91.
19. Grande DA, Singh IJ, Pugh J. Healing of experimentally produced lesions in articular cartilage following chondrocyte transplantation. Anat Rec 1987; 218: 142-8.
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20. Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med 1994; 331: 889e95.
Practice points
In assessing diseased joints and those with an implant it is an imperative to exclude infection
Infection is best diagnosed by synovial fluid analysis which must include: nucleated cell count; polymorphs expressed as a proportion of all nucleated cells; ragocytes expressed as a proportion of all nucleated cells; and the presence of haematoidin crystals
In metal-on-metal hip implants ARMD must be confirmed or excluded
Figure legends
Figure 1 Examples of different materials seen in biopsies of synovium: (a) HMWPE. (b) Cement. (c) Silastic. (d) Metal particles.
Figure 2 (a) Typical histological appearance of ALVAL with necrosis (N), Band of Macrophages (M), Lymphocyte aggregates (L). (b) Infective arthritis with polymorphs in the necrotic tissue and fibrin at the surface of the synovium.
Figure 3 (a) Naked granulomata consisting of giant cells surrounding hyaluronan in the synovium of a professional footballer treated for knee pain with hyaluronan injections. (b) Needle biopsy of the interface region between ACI derived (A) and native residual articular cartilage (N) showing good lateral biointegration.
20
Figure 1
Figure 2
21
Figure 3
22