Jan Philippe Kretzer

CD4+CD25+/highCD127low/- regulatory T cells are enriched in rheumatoid arthritis and osteoarthritis joints—analysis of frequency and phenotype in synovial membrane, synovial fluid and peripheral blood

IntroductionCD4+CD25+/highCD127low/- regulatory T cells (Tregs) play a crucial role in maintaining peripheral tolerance. Data about the frequency of Tregs in rheumatoid arthritis (RA) are contradictory and based on the analysis of peripheral blood (PB) and synovial fluid (SF). Because Tregs exert their anti-inflammatory activity in a contact-dependent manner, the analysis of synovial membrane (SM) is crucial. Published reports regarding this matter are lacking, so we investigated the distribution and phenotype of Tregs in concurrent samples of SM, SF and PB of RA patients in comparison to those of osteoarthritis (OA) patients.MethodsTreg frequency in a total of 40 patients (18 RA and 22 OA) matched for age and sex was assessed by flow cytometry. Functional status was assessed by analysis of cell surface markers representative of activation, memory and regulation.ResultsCD4+ T cells infiltrate the SM to higher frequencies in RA joints than in OA joints (Pu2009=u20090.0336). In both groups, Tregs accumulate more within the SF and SM than concurrently in PB (Pu2009<u20090.0001). Relative Treg frequencies were comparable in all compartments of RA and OA, but Treg concentration was significantly higher in the SM of RA patients (Pu2009=u20090.025). Both PB and SM Tregs displayed a memory phenotype (CD45RO+RA-), but significantly differed in activation status (CD69 and CD62L) and markers associated with Treg function (CD152, CD154, CD274, CD279 and GITR) with only minor differences between RA and OA.ConclusionsTreg enrichment into the joint compartment is not specific to inflammatory arthritis, as we found that it was similarly enriched in OA. RA pathophysiology might not be due to a Treg deficiency, because Treg concentration in SM was significantly higher in RA. Synovial Tregs represent a distinct phenotype and are activated effector memory cells (CD62L-CD69+), whereas peripheral Tregs are resting central memory cells (CD62L+CD69-).

Fracture Load for Periprosthetic Femoral Fractures in Cemented Versus Uncemented Hip Stems: An Experimental In Vitro Study

This cadaveric study examined fracture loads in cemented and uncemented hip stems. Additionally, individual data and bone quality were analyzed and correlated to fracture patterns and fracture load. Cemented or uncemented hip stems were implanted in a randomized fashion in 10 matched paired fresh-frozen femora (donor median age, 78 years, and donor median weight, 74.2 kg). Bone density was measured before the femurs were fractured under load (maximum load of 10,000 N), and fracture patterns were analyzed according to the Vancouver and Johansson classification systems. In the uncemented group, all of the femurs fractured with a median load of 2625 N (range, 1725-7647 N). In the cemented group, 5 femurs fractured with a median maximum load of 9127 N (range, 2845-10,000 N) and 5 femurs did not fracture with a maximum load of 10,000 N. Fracture load corresponded to 4 times and 8.8 times body weight in the uncemented and cemented groups, respectively. Fracture patterns corresponded to Vancouver type A fractures in uncemented stems and Vancouver type C fractures in cemented hip stems. Analysis showed a significant correlation between fracture load and bone density in the uncemented group, whereas there was no correlation in the cemented group. Patients with poor bone quality treated with an uncemented hip stem are at higher risk for periprosthetic fractures; therefore, we recommend cemented stems in this group of patients. Cementation appears to protect against periprosthetic fractures, probably from internal stiffening of the femoral cavity.

In vivo serum titanium ion levels following modular neck total hip arthroplasty--10 year results in 67 patients.

The objective of the present cross-sectional study was to determine in vivo titanium ion levels following cementless total hip arthroplasty (THA) using a modular stem system with different shapes for femoral canal fit and multiple neck options. A consecutive series of 173 patients (190 hips) who underwent cementless modular neck THA and a ceramic on polyethylene bearing with a median follow-up of 9 (7-13) years was evaluated retrospectively. According to a standardized protocol, titanium ion measurements were performed on 67 patients using high-resolution inductively coupled plasma-mass spectrometry. Ion levels were compared to a control group comprising patients with non-modular titanium implants (n=11) and to individuals without implants (n=23). Modular neck THA did not result in elevated titanium ion levels compared to non-modular THA. Compared to individuals without implants, both modular THA and non-modular THA showed elevated titanium ion levels. Absolute titanium ion levels, however, were comparatively low for both implants. The data suggest that the present modular stem system does not result in elevated systemic titanium ion levels in the medium term when compared to non-modular stems. Further longitudinal studies are needed to evaluate the use of systemic titanium ion levels as an objective diagnostic tool to identify THA failure and to monitor patients following revision surgery.

On the inflammatory response in metal-on-metal implants

BackgroundMetal-on-metal implants are a special form of hip endoprostheses that despite many advantages can entail serious complications due to release of wear particles from the implanted material. Metal wear particles presumably activate local host defence mechanisms, which causes a persistent inflammatory response with destruction of bone followed by a loosening of the implant. To better characterize this inflammatory response and to link inflammation to bone degradation, the local generation of proinflammatory and osteoclast-inducing cytokines was analysed, as was systemic T cell activation.MethodsBy quantitative RT-PCR, gene expression of cytokines and markers for T lymphocytes, monocytes/macrophages and osteoclasts, respectively, was analysed in tissue samples obtained intraoperatively during exchange surgery of the loosened implant. Peripheral T cells were characterized by cytofluorometry before surgery and 7 to 10xa0days thereafter.ResultsAt sites of osteolysis, gene expression of cathepsin K, CD14 and CD3 was seen, indicating the generation of osteoclasts, and the presence of monocytes and of T cells, respectively. Also cytokines were highly expressed, including CXCL8, IL-1ß, CXCL2, MRP-14 and CXCL-10. The latter suggest T cell activation, a notion that could be confirmed by detecting a small, though conspicuous population of activated CD4+ cells in the peripheral blood T cells prior to surgery.ConclusionOur data support the concept that metallosis is the result of a local inflammatory response, which according to histomorphology and the composition of the cellular infiltrate classifies as an acute phase of a chronic inflammatory disease. The proinflammatory environment, particularly the generation of the osteoclast-inducing cytokines CXCL8 and IL1-ß, promotes bone resorption. Loss of bone results in implant loosening, which then causes the major symptoms of metallosis, pain and reduced range of motion.

Wear in Total Knee Arthroplasty - Just a Question of Polyethylene?

PurposeBiological reactions against wear particles are a common cause for revision in total knee arthroplasty. To date, wear has mainly been attributed to polyethylene. However, the implants have large metallic surfaces that also could potentially lead to metal wear products (metal ions and debris). The aim of this study was to determine the local release of cobalt, chromium, molybdenum and titanium in total knee arthroplasty during a standard knee wear test.MethodsFour moderately conforming fixed-bearing implants were subjected to physiological loadings and motions for 5×106 walking cycles in a knee wear simulator. Polyethylene wear was determined gravimetrically and the release of metallic wear products was measured using high resolution-inductively coupled plasma-mass spectrometry.ResultsA polyethylene wear rate of 7.28u2009±u20090.27xa0mg/106xa0cycles was determined and the cumulative mass of released metals measured 1.63u2009±u20090.28xa0mg for cobalt, 0.47u2009±u20090.06xa0mg for chromium, 0.42u2009±u20090.06xa0mg for molybdenum and 1.28u2009±u20090.14xa0mg for titanium.ConclusionFor other metallic implants such as metal-on-metal total hip arthroplasty, the metal wear products can interact with the immune system, potentially leading to immunotoxic effects. In this study about 12xa0% by weight of the wear products were metallic, and these particles and ions may become clinically relevant for patients sensitive to these materials in particular. Non-metallic materials (e.g. ceramics or suitable coatings) may be considered for an alternative treatment for those patients.

Fixation of the shorter cementless GTS™ stem: biomechanical comparison between a conventional and an innovative implant design

IntroductionConventional cementless total hip arthroplasty already shows very good clinical results. Nevertheless, implant revision is often accompanied by massive bone loss. The new shorter GTS™ stem has been introduced to conserve femoral bone stock. However, no long-term clinical results were available for this implant. A biomechanical comparison of the GTS™ stem with the clinically well-established CLS® stem was therefore preformed to investigate the targeted stem philosophy.Materials and methodsFour GTS™ stems and four CLS® stems were implanted in a standardized manner in eight synthetic femurs. A high-precision measuring device was used to determine micromotions of the stem and bone during different load applications. Calculation of relative micromotions at the bone–implant interface allowed the rotational implant stability and the bending behavior of the stem to be determined.ResultsLowest relative micromotions were detected near the lesser trochanter within the proximal part of both stems. Maximum relative micromotions were measured near the distal tip of the stems, indicating a proximal fixation of both stems. For the varus–valgus–torque application, a comparable stem bending behavior was shown for both stems.ConclusionBoth stems seem to provide a comparable and adequate primary stability. The shortened GTS™ design has a comparable rotational stability and bone–implant flexibility compared to a conventional stem. This study demonstrates that the CLS® stem and the GTS™ stem exhibit similar biomechanical behavior. However, a clinical confirmation of these experimental results is still required.

Wear testing of total hip replacements under severe conditions

Controlled wear testing of total hip replacements in hip joint simulators is a well-established and powerful method, giving an extensive prediction of the long-term clinical performance. To understand the wear behavior of a bearing and its limits under in vivo conditions, testing scenarios should be designed as physiologically as possible. Currently, the ISO standard protocol 14242 is the most common preclinical testing procedure for total hip replacements, based on a simplified gait cycle for normal walking conditions. However, in recent years, wear patterns have increasingly been observed on retrievals that cannot be replicated by the current standard. The purpose of this study is to review the severe testing conditions that enable the generation of clinically relevant wear rates and phenomena. These conditions include changes in loading and activity, third-body wear, surface topography, edge wear and the role of aging of the bearing materials.

Influence of stem design on the primary stability of megaprostheses of the proximal femur

PurposeExtended bone defects of the proximal femur can be reconstructed by megaprostheses for which aseptic loosening constitutes one of the major failure modes. The basic requirement for long-term success of endoprostheses is primary stability. We therefore assessed whether sufficient primary stability can be achieved by four different megaprostheses in a standardised bone defect of the proximal femur and whether their different design leads to different fixation patterns.MethodsFour different designs of proximal femoral replacements were implanted into 16 Sawbones® after preparing segmental bone defects (AAOS type II). Primary rotational stability was analysed by application of a cyclic torque of ±7xa0Nm and measuring the relative micromotions between bone and implant at different levels. The main fixation zones and differences of fixation patterns of the stem designs were determined by an analysis of variance.ResultsAll four implants exhibited micromotions below 150xa0μm, indicating adequate primary stability. Lowest micromotions for all designs were located near the femoral isthmus. The extent of primary stability and the global implant fixation pattern differed considerably and could be related to the different design concepts.ConclusionsAll megaprostheses studied provided sufficient primary stability if the fixation conditions of the femoral isthmus were intact. The design characteristics of the different stems largely determined the extent of primary stability and fixation pattern.Understanding these different fixation types could help the surgeon to choose the most suitable implant if the fixation conditions in the isthmus are compromised.

Wear performance of ceramic-on-metal hip bearings.

Ceramic-on-metal (CoM) bearings are considered to be a promising alternative to polyethylene-based bearings or hard-on-hard bearings (Ceramic-on-Ceramic (CoC) and Metal-on-Metal (MoM)). Although, CoM shows lower wear rates than MoM, in-vitro wear testing of CoM shows widely varying results. This may be related to limitations of wear-measuring methods. Therefore, the aim of this study was to improve the gravimetric measurement technique and to test wear behaviour of CoM bearings compared to CoC bearings. Level walking according to ISO-14242 was simulated for four CoM and four CoC bearings. Prior to simulation, errors in measurement of gravimetric wear were detected and improvements in measurement technique incorporated. The results showed no differences in mean wear rates between CoM and CoC bearings. However, the CoM bearings showed wear results over a wide range of wear performance. High reliability of wear results was recorded for the CoC bearings. Material transfer was observed on the ceramic heads of the CoM bearings. Therefore, for level walking a partial mixed or boundary lubrication has to be assumed for this type of bearing. CoM is a highly sensitive wear-couple. The reasons for the observed behaviour cannot be clarified from this study. Simulator studies have to be considered as an ideal loading condition. Therefore, high variations in wear rates as seen in this study, even at low levels, may have an adverse effect on the in-vivo wear behavior. Careful clinical use may be advisable until the reasons for the variation are fully clarified and understood.

Wear testing of moderate activities of daily living using in vivo measured knee joint loading.

Resumption of daily living activities is a basic expectation for patients provided with total knee replacements. However, there is a lack of knowledge regarding the impact of different activities on the wear performance. In this study the wear performance under application of different daily activities has been analyzed. In vivo load data for walking, walking downstairs/upstairs, sitting down/standing up, and cycling (50 W & 120 W) has been standardized for wear testing. Wear testing of each activity was carried out on a knee wear simulator. Additionally, ISO walking was tested for reasons of comparison. Wear was assessed gravimetrically and wear particles were analyzed. In vivo walking produced the highest overall wear rates, which were determined to be three times higher than ISO walking. Moderate wear rates were determined for walking upstairs and downstairs. Low wear rates were determined for standing up/sitting down and cycling at power levels of 50 W and 120 W. The largest wear particles were observed for cycling. Walking based on in vivo data has been shown to be the most wear-relevant activity. Highly demanding activities (stair climbing) produced considerably less wear. Taking into account the expected number of loads, low-impact activities like cycling may have a greater impact on articular wear than highly demanding activities.