The peri-prosthetic tissue response to wear debris is complex and influenced by various factors including the size, area and number of particles. We hypothesised that the ‘biologically active area’ of all metal wear particles may predict the type of peri-prosthetic tissue response. . Peri-prosthetic tissue was sampled from 21 patients undergoing revision of a small diameter metal-on-metal (MoM) total hip arthroplasty (THA) for aseptic loosening. An enzymatic protocol was used for tissue digestion and scanning electron microscope was used to characterise particles. Equivalent circle diameters and particle areas were calculated. Histomorphometric analyses were performed on all tissue specimens. Aspirates of synovial fluid were collected for analysis of the cytokine profile analysis, and compared with a control group of patients undergoing primary THA (n = 11) and revision of a failed ceramic-on-polyethylene arthroplasty (n = 6). . The overall distribution of the size and area of the particles in both lymphocyte and non-lymphocyte-dominated responses were similar; however, the subgroup with lymphocyte-dominated peri-prosthetic tissue responses had a significantly larger total number of particles. . 14 cytokines (interleukin (IL)-1ß, IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, IL-17, interferon (IFN)-γ, and IFN-gamma-inducible protein 10), chemokines (macrophage inflammatory protein (MIP)-1α and MIP-1ß), and growth factors (granulocyte macrophage colony stimulating factor (GM-CSF) and platelet derived growth factor) were detected at significantly higher levels in patients with metal wear debris compared with the control group. . Significantly higher levels for IL-1ß, IL-5, IL-10 and GM-CSF were found in the subgroup of tissues from failed MoM THAs with a lymphocyte-dominated peri-prosthetic response compared with those without this response. . These results suggest that the ‘biologically active area’ predicts the type of peri-prosthetic tissue response. The cytokines IL-1ß, IL-5, IL-10, and GM-CSF are associated with lymphocyte-dominated tissue responses from failed small-diameter MoM THA. Cite this article: Bone Joint J 2015;97-B:917–23

Aims. The aim of this study was to evaluate blood metal ion levels, leucocyte profiles, and serum cytokines in patients with a total hip arthroplasty (THA) involving modular dual-mobility components. Patients and Methods. A total of 39 patients were recruited, with clinical follow-up of up to two years. Outcome was assessed using the Harris Hip Score (HHS, the 12-Item Short-Form Health Survey (SF-12), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and a visual analogue scale (VAS) for pain. Blood concentrations of cobalt (Co), chromium (Cr), and serum cytokines were measured. Subpopulations of leucocytes were analyzed by flow cytometry. Results. The clinical performance was good. Blood Co levels (ref 1.0 µg/l) were mildly elevated in seven patients at three months, and two patients at two years’ follow-up. The preoperative Cr levels were normal except for one patient with a detectable Cr (1.2 µg/l). Cr levels were detectable in three patients at three months, two patients at one year, and three patients at two years’ follow-up. No patients had symptoms suggestive of failure. Although flow cytometry showed constant circulating leucocyte profiles, there was a significant reduction of serum interleukin (IL)-4, IL-5, and interferon gamma (IFNγ) postoperatively compared with the preoperative levels (p < 0.05). Conclusion. These results suggest that THA using modular dual-mobility components is safe. This allows an opportunity to use a large femoral head and a thick polyethylene bearing surface, which is especially useful in revision procedures or high-risk situations when added stability is required. Cite this article: Bone Joint J 2019;101-B:1035–1041

We investigated the circulating levels of the main cytokines involved in bone resorption (IL-1β, IL-6, TNF-α), prostaglandins (PGE. 2. ) and metalloproteases (MMP-1), as possible early markers of osteolysis, in the serum of eight patients with periprosthetic osteolysis and ten patients without osteolysis. All had received a cementless hip prosthesis (ABG-1). We also assessed the serum levels of IL-11 and TGF-β anti-inflammatory cytokines exerting protective effect on bone resorption. The mean serum levels of IL-1β, IL-6, TNF-α, TGF-β, MMP-1, and PGE. 2. in patients with periprosthetic osteolysis did not differ significantly from those of patients without osteolysis or from those of normal controls. IL-11 serum levels were not detectable at all in any of the patients, while they were detected within normal reference values in the control subjects (significant inverse correlation). We believe that circulating cytokines cannot be regarded as markers of osteolysis, a condition characterised by a local inflammation without systemic signs of inflammation. On the contrary, the undetectable levels of IL-11 in implanted patients could provide evidence for a lack of balance between pro- and anti-inflammatory cytokines in these patients

Frozen shoulder is a chronic fibrosing condition of the capsule of the joint. The predominant cells involved are fibroblasts and myofibroblasts which lay down a dense matrix of type-I and type-III collagen within the capsule. This subsequently contracts leading to the typical features of pain and stiffness. Cytokines and growth factors regulate the growth and function of the fibroblasts of connective tissue and remodelling of the matrix is controlled by the matrix metalloproteinases (MMPs) and their inhibitors. Our aim was to determine whether there was an abnormal expression or secretion of cytokines, growth factors and MMPs in tissue samples from 14 patients with frozen shoulder using the reverse transcription/polymerase chain reaction (RT/PCR) technique and to compare the findings with those in tissue from four normal control shoulders and from five patients with Dupuytren’s contracture. Tissue from frozen shoulders demonstrated the presence of mRNA for a large number of cytokines and growth factors although the frequency was only slightly higher than in the control tissue. The frequency for a positive signal for the proinflammatory cytokines Il-1β and TNF-α and TNF-β, was not as great as in the Dupuytren’s tissue. The presence of mRNA for fibrogenic growth factors was, however, more similar to that obtained in the control and Dupuytren’s tissue. This correlated with the histological findings which in most specimens showed a dense fibrous tissue response with few cells other than mature fibroblasts and with very little evidence of any active inflammatory cell process. Positive expressions of the mRNA for the MMPs were also increased, together with their natural inhibitor TIMP. The notable exception compared with control and Dupuytren’s tissue was the absence of MMP-14, which is known to be a membrane-type MMP required for the activation of MMP-2 (gelatinase A). Understanding the control mechanisms which play a part in the pathogenesis of frozen shoulder may lead to the development of new regimes of treatment for this common, protracted and painful chronic fibrosing condition

Particulate prosthetic materials are often studied by adding them to monocytic cells in vitro and measuring the release of cytokines as an indicator of their inflammatory potential. Endotoxin is known to be a contaminant of particle preparations and also stimulates the release of cytokines. It is usual to use a proprietary endotoxin test to avoid erroneous results. Four different formulations of cement were found to be free from endotoxin using standard, gelclot tests but stimulated different levels of release of cytokines from macrophages. These differences were explained when a more sensitive, kinetic endotoxin assay showed that release correlated with minor contamination with endotoxin. In a repeat experiment using cement particles with low or undetectable levels of endotoxin by kinetic assay, differences in the ability of the formulations to stimulate the release of cytokines were not seen. Endotoxin is adsorbed on to the surface of particles and it is this combination which stimulates increased release of cytokines. In both the above methods for determination of endotoxin, the water in which the particles had been soaked was examined rather than the particles directly. Further investigations showed that a kinetic assay directly on a particle suspension is the most sensitive method to measure contamination with endotoxin

The tissues surrounding 65 cemented and 36 cementless total joint replacements undergoing revision were characterised for cell types by immunohistochemistry and for cytokine expression by in situ hybridisation. We identified three distinct groups of revised implants: loose implants with ballooning radiological osteolysis, loose implants without osteolysis, and well-fixed implants. In the cemented series, osteolysis was associated with increased numbers of macrophages (p = 0.0006), T-lymphocyte subgroups (p = 0.03) and IL-1 (p = 0.02) and IL-6 (p = 0.0001) expression, and in the cementless series with increased numbers of T-lymphocyte subgroups (p = 0.005) and increased TNFα expression (p = 0.04). For cemented implants, the histological, histochemical and cytokine profiles of the interface correlated with the clinical and radiological grade of loosening and osteolysis. Our findings suggest that there are different biological mechanisms of loosening and osteolysis for cemented and cementless implants. T-lymphocyte modulation of macrophage function may be an important interaction at prosthetic interfaces

Our aim was to determine if the serum levels of bone-resorbing cytokines (IL-1β, TNF-α, IL-6, GM-CSF) are altered in patients with aseptic loosening of a total hip prosthesis, and if such levels are influenced by the type of implant. We determined cytokine levels in sera from 35 patients before revision for failed total hip arthroplasty and compared them with those in 25 healthy donors. We also assessed the soluble receptor of interleukin-2 (sIL-2r) in serum as an indication of a specific immune reaction against the implant. Our findings showed that the sIL-2r and TNF-α serum level did not change. The IL-6 level was not significantly altered, but was higher in patients with TiAlV prostheses than in those with a CrCoMo implant and in patients with cemented prostheses. The IL-1β level was found to be higher in those with a TiAlV cemented prosthesis than in the control group (p = 0.0001) and other groups of patients (p = 0.003 v uncemented TiAlV, p = 0.01 v cemented CrCoMo, p = 0.001 v uncemented CrCoMo). The GM-CSF level significantly increased in patients compared with healthy subjects (p = 0.008), and it was higher in those with cemented than with uncemented implants (p = 0.01). Only patients with cementless CrCoMo prostheses had levels of GM-CSF similar to those of the control group. The highest GM-CSF concentrations were observed in patients treated with non-steroidal anti-inflammatory drugs (NSAIDs) in the last months before revision (p = 0.04). In addition, when massive osteolysis was observed, the level of GM-CSF tended to decrease to that of the control group

Proponents of the biological theory of aseptic loosening have in recent years tended to concentrate on the production and distribution of particulate ultra-high-molecular-weight polyethylene (UHMWPE) debris around the potential joint space. However, mechanical loading of cemented implants with the differing elastic moduli of metal stems, polymethylmethacrylate (PMMA) cement and bone can result in relative micromotion, implying the potential for production of metal and PMMA particles from the stem-cement interface by fretting wear. In order to investigate the production and biological reactivity of debris from this interface, PMMA and metal particulate debris was produced by sliding wear of PMMA pins containing barium sulphate and zirconium dioxide against a Vaquasheened stainless steel counterface. This debris was characterised by SEM, energy-dispersive analysis by X-ray (EDAX) and image analysis, then added to cell cultures of a human monocytic cell line, U937, and stimulation of pro-osteolytic cytokines measured by ELISA. Large quantities of PMMA cement debris were generated by the sliding wear of PMMA pins against Vaquasheened stainless steel plates in the method developed for this study. Both cements stimulated the release of pro-osteolytic TNFα from the U937 monocytic cell line, in a dose-dependent fashion. There was a trend towards greater TNFα release with Palacos cement than CMW cement at the same dose. Palacos particles also caused significant release of IL-6, another pro-osteolytic cytokine, while CMW did not. The particulate cement debris produced did not stimulate the release of GM-CSF or IL1β from the U937 cells. These results may explain the cytokine pathway responsible for bone resorption caused by particulate PMMA debris. Radio-opaque additives are of value in surgical practice and clinical studies to quantify the relevance of these in vitro findings are required before the use of cement containing radio-opacifier is constrained

Aims. Chronic conditions of the wrist may be difficult to manage because pain and psychiatric conditions are correlated with abnormal function of the hand. Additionally, intra-articular inflammatory cytokines may cause pain. We aimed to validate the measurement of inflammatory cytokines in these conditions and identify features associated with symptoms. Patients and Methods. The study included 38 patients (18 men, 20 women, mean age 43 years) with a chronic condition of the wrist who underwent arthroscopy. Before surgery, the Self-Rating Depression Scale (SDS), Hand20 questionnaire and a visual analogue scale (VAS) for pain were used. Cytokine and chemokine levels in the synovial fluid of the wrist were measured using enzyme-linked immunosorbent assays and correlations between the levels with pain were analysed. Gene expression profiles of the synovial membranes were assessed using quantitative polymerase chain reaction. Results. Older patients had high pre-operative Hand20 scores. One-year post-operative Hand20 and VAS scores and pre-operative VAS scores correlated with SDS scores. Post-operative VAS scores negatively correlated with the expression of nerve growth factor and SDS scores positively correlated with the expression of tumour necrosis factor-alpha and negatively correlated with the expression of tumour necrosis factor-converting enzyme. Conclusion. There was a positive correlation between depression and chronic conditions of the wrist. Levels of some cytokines correlate with pain and depression. Additionally, cytokines may be important in the assessment and treatment of chronic conditions of the wrist and depression. Cite this article: Bone Joint J 2016;98-B:961–8

We analysed synovial fluid from 88 hips, 38 with osteoarthritis and 12 with well-functioning and 38 with loose hip prostheses. The levels of TNF-α, IL-1ß (71 hips) and IL-6 (45 hips) were measured using the ELISA technique. Joints with well-functioning or loose prostheses had significantly increased levels of TNF-α compared with those with osteoarthritis. Hips with aseptic loosening also had higher levels of IL-1ß but not of IL-6 compared with those without an implant. The levels of TNF-α and IL-1ß did not differ between hips with stable and loose prostheses. Higher levels of TNF-α were found in hips with bone resorption of type II and type III (Gustilo-Pasternak) compared with those with type-I loosening. The level of cytokines in joint fluid was not influenced by the time in situ of the implants or the age, gender or area of the osteolysis as measured on conventional radiographs. Our findings support the theory that macrophages in the joint capsule increase the production of TNF-α at an early phase probably because of particle load and in the absence of clinical loosening. Since TNF-α has an important role in the osteolytic process, the interfaces should be protected from penetration of joint fluid

Although the response of macrophages to polyethylene debris has been widely studied, it has never been compared with the cellular response to ceramic debris. Our aim was to investigate the cytotoxicity of ceramic particles (Al. 2. O. 3. and ZrO. 2. ) and to analyse their ability to stimulate the release of inflammatory mediators compared with that of high-density polyethylene particles (HDP). We analysed the effects of particle size, concentration and composition using an in vitro model. The J774 mouse macrophage cell line was exposed to commercial particles in the phagocytosable range (up to 4.5 μm). Al. 2. O. 3. was compared with ZrO. 2. at 0.6 μm and with HDP at 4.5 μm. Cytotoxicity tests were performed using flow cytometry and macrophage cytokine release was measured by ELISA. Cell mortality increased with the size and concentration of Al. 2. O. 3. particles. When comparing Al. 2. O. 3. and ZrO. 2. at 0.6 μm, we did not detect any significant difference at the concentrations analysed (up to 2500 particles per macrophage), and mortality remained very low (less than 10%). Release of TNF-α also increased with the size and concentration of Al. 2. O. 3. particles, reaching 195% of control (165 pg/ml v 84 pg/ml) at 2.4 μm and 350 particles per cell (p < 0.05). Release of TNF-α was higher with HDP than with Al. 2. O. 3. particles at 4.5 μm. However, we did not detect any significant difference in the release of TNF-α between Al. 2. O. 3. and ZrO. 2. at 0.6 μm (p > 0.05). We saw no evidence of release of interleukin-1α or interleukin-1ß after exposure to ceramic or HDP particles

Aims. Knee osteoarthritis (OA) is characterized by a chronic inflammatory process involving multiple cytokine pathways, leading to articular cartilage degeneration. Intra-articular therapies using pharmaceutical or autologous anti-inflammatory factors offer potential non-surgical treatment options. Autologous protein solution (APS) is one such product that uses the patient’s blood to produce a concentrate of cells and anti-inflammatory cytokines. This study evaluated the effect of a specific APS intra-articular injection (nSTRIDE) on patient-reported outcome measures compared to saline in moderate knee OA. Methods. A parallel, double-blinded, placebo-controlled randomized controlled trial was conducted, where patients with unilateral moderate knee OA (Kellgren-Lawrence grade 2 or 3) received either nSTRIDE or saline (placebo) injection to their symptomatic knee. The primary outcome was the difference in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score at 12 months post-intervention. Secondary outcomes included WOMAC component scores, Knee injury and Osteoarthritis Outcome Score (KOOS), and visual analogue scale (VAS) scores at all follow-up timepoints (three, six, and 12 months). Results. A total of 40 patients were analyzed (21 nSTRIDE; 19 saline) in the study. No significant difference was found between nSTRIDE and saline groups for WOMAC total score at 12 months (mean difference -10.4 (95% CI -24.4 to 3.6; p = 0.141). There were no significant differences in WOMAC or KOOS scores across all timepoints. VAS scores favoured the saline group for both rest and worst pain scales at 12 months post-injection (mean difference (worst) 12 months 21.5 (95% CI 6.2 to 36.8; p = 0.008); mean difference (rest) 12 months 17.8 (95% CI 2.2 to 33.4; p = 0.026)). There were no adverse events recorded in either study group. Conclusion. Our study demonstrates no significant differences between nSTRIDE and saline groups in KOOS and WOMAC scores over time. Notably, APS injection resulted in significantly worse pain symptoms at 12 months compared to saline injection. Cite this article: Bone Joint J 2024;106-B(9):907–915

The role of inflammatory cells and their products in tendinopathy is not completely understood. Pro-inflammatory cytokines are upregulated after oxidative and other forms of stress. Based on observations that increased cytokine expression has been demonstrated in cyclically-loaded tendon cells we hypothesised that because of their role in oxidative stress and apoptosis, pro-inflammatory cytokines may be present in rodent and human models of tendinopathy. A rat supraspinatus tendinopathy model produced by running overuse was investigated at the genetic level by custom micro-arrays. Additionally, samples of torn supraspinatus tendon and matched intact subscapularis tendon were collected from patients undergoing arthroscopic shoulder surgery for rotator-cuff tears and control samples of subscapularis tendon from ten patients with normal rotator cuffs undergoing arthroscopic stabilisation of the shoulder were also obtained. These were all evaluated using semiquantitative reverse transcription polymerase chain-reaction and immunohistochemistry. We identified significant upregulation of pro-inflammatory cytokines and apoptotic genes in the rodent model (p = 0.005). We further confirmed significantly increased levels of cytokine and apoptotic genes in human supraspinatus and subscapularis tendon harvested from patients with rotator cuff tears (p = 0.0008). These findings suggest that pro-inflammatory cytokines may play a role in tendinopathy and may provide a target for preventing tendinopathies

Aims. Early evidence has emerged suggesting that ceramic-on-ceramic articulations induce a different tissue reaction to ceramic-on-polyethylene and metal-on-metal bearings. Therefore, the aim of this study was to investigate the tissue reaction and cellular response to ceramic total hip arthroplasty (THA) materials in vitro, as well as the tissue reaction in capsular tissue after revision surgery of ceramic-on-ceramic THAs. Patients and Methods. We investigated tissue collected at revision surgery from nine ceramic-on-ceramic articulations. we compared our findings with tissue obtained from five metal-on-metal THA revisions, four ceramic-on-polyethylene THAs, and four primary osteoarthritis synovial membranes. The latter were analyzed to assess the amount of tissue fibrosis that might have been present at the time of implantation to enable evaluation, in relation to implantation time, of any subsequent response in the tissues. Results. There was a significant increase in tissue fibrosis with implantation time for all implant types tested. Interestingly, the tissue fibrosis in ceramic-on-ceramic THAs was significantly increased compared with metal-on-metal and ceramic-on-polyethylene. Additionally, we found ceramic wear particles in the periprosthetic tissue of ceramic implants. Fibroblasts responded with expression of cytokines when cultured on alumina-toughened zirconia (ATZ) and zirconia-toughened alumina (ZTA) ceramic surfaces. This response was more pronounced on ATZ ceramics compared with ZTA ceramics. The same inflammatory response was observed with peripheral blood mononuclear cells (PBMCs) cultured on ZTA and ATZ. Conclusion. Our findings therefore, corroborate the previous findings that ceramic-on-ceramic periprosthetic revision tissue is fibrous and offer an explanation for this observation. We detected a long-term inflammatory response of PBMCs and an inflammatory response of fibroblasts to ATZ and ZTA ceramic. These findings partially explain the fibrotic tissue change in periprosthetic tissue of ceramic-on-ceramic bearings. Cite this article: Bone Joint J 2018;100-B:882–90

Rotator cuff tears are common in middle-aged and elderly patients. Despite advances in the surgical repair of rotator cuff tears, the rates of recurrent tear remain high. This may be due to the complexity of the tendons of the rotator cuff, which contributes to an inherently hostile healing environment. During the past 20 years, there has been an increased interest in the use of biologics to complement the healing environment in the shoulder, in order to improve rotator cuff healing and reduce the rate of recurrent tears. The aim of this review is to provide a summary of the current evidence for the use of forms of biological augmentation when repairing rotator cuff tears.

Cite this article: Bone Joint J 2024;106-B(9):978–985.

Aims

Metal and ceramic humeral head bearing surfaces are available choices in anatomical shoulder arthroplasties. Wear studies have shown superior performance of ceramic heads, however comparison of clinical outcomes according to bearing surface in total shoulder arthroplasty (TSA) and hemiarthroplasty (HA) is limited. This study aimed to compare the rates of revision and reoperation following metal and ceramic humeral head TSA and HA using data from the National Joint Registry (NJR), which collects data from England, Wales, Northern Ireland, Isle of Man and the States of Guernsey.

Aims

The aim was to assess whether robotic-assisted total knee arthroplasty (rTKA) had greater knee-specific outcomes, improved fulfilment of expectations, health-related quality of life (HRQoL), and patient satisfaction when compared with manual TKA (mTKA).

Aims

The primary aim was to assess whether robotic total knee arthroplasty (rTKA) had a greater early knee-specific outcome when compared to manual TKA (mTKA). Secondary aims were to assess whether rTKA was associated with improved expectation fulfilment, health-related quality of life (HRQoL), and patient satisfaction when compared to mTKA.

Aims

To determine whether platelet-rich plasma (PRP) injection improves outcomes two years after acute Achilles tendon rupture.

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