Tissue responses to debris formed by abrasion of polymethylmethacrylate
(PMMA) spacers at two-stage revision arthroplasty for prosthetic
joint infection are not well described. We hypothesised that PMMA
debris induces immunomodulation in periprosthetic tissues. Samples of tissue were taken during 35 two-stage revision arthroplasties
(nine total hip and 26 total knee arthroplasties) in patients whose
mean age was 67 years (44 to 85). Fourier transform infrared microscopy
was used to confirm the presence of PMMA particles. Histomorphometry
was performed using Sudan Red and Haematoxylin-Eosin staining.
CD-68, CD-20, CD-11(c), CD-3 and IL-17 antibodies were used to immunophenotype
the inflammatory cells. All slides were scored semi-quantitatively
using the modified Willert scoring system.Aims
Patients and Methods
We explored the literature surrounding whether
allergy and hypersensitivity has a clinical basis for implant selection
in total knee arthroplasty (TKA). In error, the terms hypersensitivity
and allergy are often used synonymously. Although a relationship
is present, we could not find any evidence of implant failure due
to allergy. There is however increasing basic science that suggests
a link between loosening and metal ion production. This is not an
allergic response but is a potential problem. With a lack of evidence
logically there can be no justification to use ‘hypoallergenic’
implants in patients who have pre-existing skin sensitivity to the
metals used in TKA. Cite this article:
Pathological assessment of periprosthetic tissues is important, not only for diagnosis, but also for understanding the pathobiology of implant failure. The host response to wear particle deposition in periprosthetic tissues is characterised by cell and tissue injury, and a reparative and inflammatory response in which there is an innate and adaptive immune response to the material components of implant wear. Physical and chemical characteristics of implant wear influence the nature of the response in periprosthetic tissues and account for the development of particular complications that lead to implant failure, such as osteolysis which leads to aseptic loosening, and soft-tissue necrosis/inflammation, which can result in pseudotumour formation. The innate response involves phagocytosis of implant-derived wear particles by macrophages; this is determined by pattern recognition receptors and results in expression of cytokines, chemokines and growth factors promoting inflammation and osteoclastogenesis; phagocytosed particles can also be cytotoxic and cause cell and tissue necrosis. The adaptive immune response to wear debris is characterised by the presence of lymphoid cells and most likely occurs as a result of a cell-mediated hypersensitivity reaction to cell and tissue components altered by interaction with the material components of particulate wear, particularly metal ions released from cobalt-chrome wear particles. Cite this article: Professor N. A. Athanasou. The pathobiology and pathology of aseptic implant failure.
The continual cycle of bone formation and resorption
is carried out by osteoblasts, osteocytes, and osteoclasts under
the direction of the bone-signaling pathway. In certain situations
the host cycle of bone repair is insufficient and requires the assistance
of bone grafts and their substitutes. The fundamental properties
of a bone graft are osteoconduction, osteoinduction, osteogenesis,
and structural support. Options for bone grafting include autogenous
and allograft bone and the various isolated or combined substitutes
of calcium sulphate, calcium phosphate, tricalcium phosphate, and
coralline hydroxyapatite. Not all bone grafts will have the same
properties. As a result, understanding the requirements of the clinical
situation and specific properties of the various types of bone grafts
is necessary to identify the ideal graft. We present a review of
the bone repair process and properties of bone grafts and their
substitutes to help guide the clinician in the decision making process. Cite this article:
External fixation is widely used in orthopaedic
and trauma surgery. Infections around pin or wire sites, which are usually
localised, non-invasive, and are easily managed, are common. Occasionally,
more serious invasive complications such as necrotising fasciitis
(NF) and toxic shock syndrome (TSS) may occur. We retrospectively reviewed all patients who underwent external
fixation between 1997 and 2012 in our limb lengthening and reconstruction
programme. A total of eight patients (seven female and one male)
with a mean age of 20 years (5 to 45) in which pin/wire track infections
became limb- or life-threatening were identified. Of these, four
were due to TSS and four to NF. Their management is described. A
satisfactory outcome was obtained with early diagnosis and aggressive
medical and surgical treatment. Clinicians caring for patients who have external fixation and
in whom infection has developed should be aware of the possibility
of these more serious complications. Early diagnosis and aggressive
treatment are required in order to obtain a satisfactory outcome. Cite this article:
MicroRNAs (miRNAs ) are small non-coding RNAs
that regulate gene expression. We hypothesised that the functions
of certain miRNAs and changes to their patterns of expression may
be crucial in the pathogenesis of nonunion. Healing fractures and
atrophic nonunions produced by periosteal cauterisation were created
in the femora of 94 rats, with 1:1 group allocation. At post-fracture
days three, seven, ten, 14, 21 and 28, miRNAs were extracted from
the newly generated tissue at the fracture site. Microarray and
real-time polymerase chain reaction (PCR) analyses of day 14 samples
revealed that five miRNAs, miR-31a-3p, miR-31a-5p, miR-146a-5p,
miR-146b-5p and miR-223-3p, were highly upregulated in nonunion.
Real-time PCR analysis further revealed that, in nonunion, the expression
levels of all five of these miRNAs peaked on day 14 and declined
thereafter. Our results suggest that miR-31a-3p, miR-31a-5p, miR-146a-5p,
miR-146b-5p and miR-223-3p may play an important role in the development
of nonunion. These findings add to the understanding of the molecular mechanism
for nonunion formation and may lead to the development of novel
therapeutic strategies for its treatment. Cite this article:
We have undertaken a prospective study in patients with a fracture of the femoral shaft requiring intramedullary nailing to test the hypothesis that the femoral canal could be a potential source of the second hit phenomenon. We determined the local femoral intramedullary and peripheral release of interleukin-6 (IL-6) after fracture and subsequent intramedullary reaming. In all patients, the fracture caused a significant increase in the local femoral concentrations of IL-6 compared to a femoral control group. The concentration of IL-6 in the local femoral environment was significantly higher than in the patients own matched blood samples from their peripheral circulation. The magnitude of the local femoral release of IL-6 after femoral fracture was independent of the injury severity score and whether the fracture was closed or open. In patients who underwent intramedullary reaming of the femoral canal a further significant local release of IL-6 was demonstrated, providing evidence that intramedullary reaming can cause a significant local inflammatory reaction.
The February 2015 Research Roundup360 looks at: Markers of post-traumatic ankle arthritis; Mangoes, trees and Solomon Islanders; Corticosteroid injection and ulnar neuropathy; Moral decision-making: the secret skill?; Biomechanical studies under the spotlight; Anaesthetic risk and hip replacement
The aim of this study was to assess the role
of synovial C-reactive protein (CRP) in the diagnosis of chronic periprosthetic
hip infection. We prospectively collected synovial fluid from 89
patients undergoing revision hip arthroplasty and measured synovial
CRP, serum CRP, erythrocyte sedimentation rate (ESR), synovial white
blood cell (WBC) count and synovial percentages of polymorphonuclear
neutrophils (PMN). Patients were classified as septic or aseptic
by means of clinical, microbiological, serum and synovial fluid
findings. The high viscosity of the synovial fluid precluded the
analyses in nine patients permitting the results in 80 patients
to be studied. There was a significant difference in synovial CRP
levels between the septic (n = 21) and the aseptic (n = 59) cohort.
According to the receiver operating characteristic curve, a synovial
CRP threshold of 2.5 mg/l had a sensitivity of 95.5% and specificity
of 93.3%. The area under the curve was 0.96. Compared with serum
CRP and ESR, synovial CRP showed a high diagnostic value. According
to these preliminary results, synovial CRP may be a useful parameter
in diagnosing chronic periprosthetic hip infection. Cite this article:
The aim of this study was to assess the effect
of injecting genetically engineered chondrocytes expressing transforming
growth factor beta 1 (TGF-β1) into the knees of patients with osteoarthritis.
We assessed the resultant function, pain and quality of life. A total of 54 patients (20 men, 34 women) who had a mean age
of 58 years (50 to 66) were blinded and randomised (1:1) to receive
a single injection of the active treatment or a placebo. We assessed
post-treatment function, pain severity, physical function, quality
of life and the incidence of treatment-associated adverse events. Patients
were followed at four, 12 and 24 weeks after injection. At final follow-up the treatment group had a significantly greater
improvement in the mean International Knee Documentation Committee
score than the placebo group (16 points; -18 to 49, This technique may result in improved clinical outcomes, with
the aim of slowing the degenerative process, leading to improvements
in pain and function. However, imaging and direct observational
studies are needed to verify cartilage regeneration. Nevertheless,
this study provided a sufficient basis to proceed to further clinical testing. Cite this article:
No previous studies have examined the physical
characteristics of patients with cauda equina syndrome (CES). We compared
the anthropometric features of patients who developed CES after
a disc prolapse with those who did not but who had symptoms that
required elective surgery. We recorded the age, gender, height,
weight and body mass index (BMI) of 92 consecutive patients who
underwent elective lumbar discectomy and 40 consecutive patients who
underwent discectomy for CES. On univariate analysis, the mean BMI
of the elective discectomy cohort (26.5 kg/m2 (16.6 to
41.7) was very similar to that of the age-matched national mean
(27.6 kg/m2, p = 1.0). However, the mean BMI of the CES
cohort (31.1 kg/m2 (21.0 to 54.9)) was significantly
higher than both that of the elective group (p <
0.001) and the
age-matched national mean (p <
0.001). A similar pattern was
seen with the weight of the groups. Multivariate logistic regression
analysis was performed, adjusted for age, gender, height, weight
and BMI. Increasing BMI and weight were strongly associated with
an increased risk of CES (odds ratio (OR) 1.17, p <
0.001; and
OR 1.06, p <
0.001, respectively). However, increasing height
was linked with a reduced risk of CES (OR 0.9, p <
0.01). The
odds of developing CES were 3.7 times higher (95% confidence interval
(CI) 1.2 to 7.8, p = 0.016) in the overweight and obese (as defined
by the World Health Organization: BMI ≥ 25 kg/m2) than
in those of ideal weight. Those with very large discs (obstructing
>
75% of the spinal canal) had a larger BMI than those with small
discs (obstructing <
25% of the canal; p <
0.01). We therefore
conclude that increasing BMI is associated with CES.
Abnormal wear of cobalt-containing metal-on-metal
joints is associated with inflammatory pseudotumours. Cobalt ions
activate human toll-like receptor 4 (TLR4), which normally responds
to bacterial lipopolysaccharide (LPS) in sepsis. Activation of TLR4
by LPS increases the expression of chemokines IL-8 and CXCL10, which
recruit leukocytes and activated T-cells, respectively. This study
was designed to determine whether cobalt induces a similar inflammatory
response to LPS by promoting the expression of IL-8 and CXCL10.
A human monocytic cell line, derived from acute monocytic leukaemia,
was treated with cobalt ions and expression of IL-8 and CXCL10 measured at
mRNA and protein levels. Cobalt-treated macrophages showed a 60-fold
increase in IL-8 mRNA, and an eightfold increase in production of
the mature chemokine (both p <
0.001); expression of the CXCL10
gene and protein was also significantly increased by cobalt (both
p <
0.001). Experiments were also performed in the presence of
CLI-095, a TLR4-specific antagonist which abrogated the cobalt-mediated
increase in IL-8 and CXCL10 expression. These findings suggest that cobalt ions induce inflammation similar
to that observed during sepsis by the simultaneous activation of
two TLR4-mediated signalling pathways. These pathways result in
increased production of IL-8 and CXCL10, and may be implicated in
pseudotumour formation following metal-on-metal replacement. Cite this article:
A 70-year-old man with an uncemented metal-on-polyethylene
total hip prosthesis underwent revision arthroplasty 33 months later
because of pain, swelling and recurrent dislocation. There appeared
to be corrosion and metal release from the prosthetic head, resulting
in pseudotumour formation and severe local soft-tissue destruction.
The corrosion occurred at the junction between the titanium-molybdenum-zirconium-iron
taper and the cobalt-chrome-molybdenum head, but the mechanism was unproven.
Nanotechnology is the study, production and controlled
manipulation of materials with a grain size <
100 nm. At this
level, the laws of classical mechanics fall away and those of quantum
mechanics take over, resulting in unique behaviour of matter in
terms of melting point, conductivity and reactivity. Additionally,
and likely more significant, as grain size decreases, the ratio
of surface area to volume drastically increases, allowing for greater interaction
between implants and the surrounding cellular environment. This
favourable increase in surface area plays an important role in mesenchymal
cell differentiation and ultimately bone–implant interactions. Basic science and translational research have revealed important
potential applications for nanotechnology in orthopaedic surgery,
particularly with regard to improving the interaction between implants
and host bone. Nanophase materials more closely match the architecture
of native trabecular bone, thereby greatly improving the osseo-integration
of orthopaedic implants. Nanophase-coated prostheses can also reduce
bacterial adhesion more than conventionally surfaced prostheses.
Nanophase selenium has shown great promise when used for tumour
reconstructions, as has nanophase silver in the management of traumatic
wounds. Nanophase silver may significantly improve healing of peripheral
nerve injuries, and nanophase gold has powerful anti-inflammatory
effects on tendon inflammation. Considerable advances must be made in our understanding of the
potential health risks of production, implantation and wear patterns
of nanophase devices before they are approved for clinical use.
Their potential, however, is considerable, and is likely to benefit
us all in the future. Cite this article:
Peri-prosthetic osteolysis and subsequent aseptic
loosening is the most common reason for revising total hip replacements.
Wear particles originating from the prosthetic components interact
with multiple cell types in the peri-prosthetic region resulting
in an inflammatory process that ultimately leads to peri-prosthetic
bone loss. These cells include macrophages, osteoclasts, osteoblasts
and fibroblasts. The majority of research in peri-prosthetic osteolysis
has concentrated on the role played by osteoclasts and macrophages.
The purpose of this review is to assess the role of the osteoblast
in peri-prosthetic osteolysis. In peri-prosthetic osteolysis, wear particles may affect osteoblasts
and contribute to the osteolytic process by two mechanisms. First,
particles and metallic ions have been shown to inhibit the osteoblast
in terms of its ability to secrete mineralised bone matrix, by reducing
calcium deposition, alkaline phosphatase activity and its ability
to proliferate. Secondly, particles and metallic ions have been
shown to stimulate osteoblasts to produce pro inflammatory mediators Cite this article:
The use of platelet-rich plasma (PRP) as an adjuvant
to tissue repair is gaining favour in orthopaedic surgery. Tunnel widening
after anterior cruciate ligament (ACL) reconstruction is a recognised
phenomenon that could compromise revision surgery. The purpose of
this study was to determine whether PRP might prevent tunnel widening
in ACL reconstruction. Patients undergoing ACL reconstruction using a hamstring graft
were randomly allocated either to have PRP introduced into the tunnels
peri-operatively or not. CT scanning of the knees was carried out
on the day after surgery and at three months post-operatively and
the width of the tunnels was measured. Patients were also evaluated
clinically at three months, when laxity was also measured. Each group comprised 25 patients, and at three months post-operatively
all were pain-free with stable knees, a negative Lachman test and
a good range of movement. Arthrometric results had improved significantly
in both groups (p <
0.001). Despite slightly less tunnel widening
in the PRP group, there was no significant difference between the
groups at the femoral opening or the mid-tunnel (p = 0.370 and p
= 0.363, respectively) nor at the tibial opening or mid-tunnel (p
= 0.333 and p = 0.177, respectively). We conclude that PRP has no significant effect in preventing
tunnel widening after ACL reconstruction. Cite this article:
The incidence of acute and chronic conditions
of the tendo Achillis appear to be increasing. Causation is multifactorial
but the role of inherited genetic elements and the influence of
environmental factors altering gene expression are increasingly
being recognised. Certain individuals’ tendons carry specific variations
of genetic sequence that may make them more susceptible to injury.
Alterations in the structure or relative amounts of the components
of tendon and fine control of activity within the extracellular
matrix affect the response of the tendon to loading with failure
in certain cases. This review summarises present knowledge of the influence of
genetic patterns on the pathology of the tendo Achillis, with a
focus on the possible biological mechanisms by which genetic factors
are involved in the aetiology of tendon pathology. Finally, we assess
potential future developments with both the opportunities and risks
that they may carry. Cite this article:
We evaluated the possible induction of a systemic immune response to increase anti-tumour activity by the re-implantation of destructive tumour tissue treated by liquid nitrogen in a murine osteosarcoma (LM8) model. The tumours were randomised to treatment by excision alone or by cryotreatment after excision. Tissue from the tumour was frozen in liquid nitrogen, thawed in distilled water and then re-implanted in the same animal. In addition, some mice received an immunological response modifier of OK-432 after treatment. We measured the levels of interferon-gamma and interleukin-12 cytokines and the cytotoxicity activity of splenocytes against murine LM8 osteosarcoma cells. The number of lung and the size of abdominal metastases were also measured. Re-implantation of tumour tissue after cryotreatment activated immune responses and inhibited metastatic tumour growth. OK-432 synergistically enhanced the anti-tumour effect. Our results suggest that the treatment of malignant bone tumours by reconstruction using autografts containing tumours which have been treated by liquid nitrogen may be of clinical value.