Tobias Gotterbarm

First-generation autologous chondrocyte implantation in patients with cartilage defects of the knee: 7 to 14 years' clinical and magnetic resonance imaging follow-up evaluation.

PURPOSE The purpose of this study was to evaluate the overall long-term improvement of autologous chondrocyte implantation (ACI) treatment in terms of patient satisfaction, clinical assessment, and magnetic resonance imaging (MRI) evaluation. Furthermore, we aimed to assess the impact of independent variables on clinical outcomes and patient satisfaction. METHODS We evaluated 23 patients (mean age, 30.5 ± 8.2 years) with full-thickness chondral lesions of the distal femur who underwent first-generation ACI with periosteum between 1997 and 2004. The Lysholm score, Tegner activity score, subjective International Knee Documentation Committee score, numeric rating scale score, and Short Form 36 score were used for clinical assessment preoperatively, at 1 year postoperatively, and at 7 to 14 years (mean, 9.9 years) after surgery. MRI was performed to evaluate the cartilage preoperatively and at final follow-up, by use of the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score. RESULTS ACI resulted in a substantial improvement in all clinical outcome parameters, even as much as 14 years after implantation, although a small deterioration was noticed between intermediate and final evaluations in some outcome parameters. Of the patients, 73.1% stated that they would undergo the operation again. Younger patients with a shorter duration of preoperative symptoms and smaller defect sizes benefited most. MRI findings confirmed complete defect filling in 52.3% of the patients at final follow-up. CONCLUSIONS Our long-term results confirm that first-generation ACI is an effective treatment for large full-thickness chondral and osteochondral lesions of the knee joint. Younger patients with a shorter duration of preoperative symptoms and smaller defect size benefited most in our study. LEVEL OF EVIDENCE Level IV, therapeutic case series.

Femoral offset is underestimated on anteroposterior radiographs of the pelvis but accurately assessed on anteroposterior radiographs of the hip

The aim of this retrospective cohort study was to identify any difference in femoral offset as measured on pre-operative anteroposterior (AP) radiographs of the pelvis, AP radiographs of the hip and corresponding CT scans in a consecutive series of 100 patients with primary end-stage osteoarthritis of the hip (43 men and 57 women with a mean age of 61 years (45 to 74) and a mean body mass index of 28 kg/m(2) (20 to 45)). Patients were positioned according to a standardised protocol to achieve reproducible projection and all images were calibrated. Inter- and intra-observer reliability was evaluated and agreement between methods was assessed using Bland-Altman plots. In the entire cohort, the mean femoral offset was 39.0 mm (95% confidence interval (CI) 37.4 to 40.6) on radiographs of the pelvis, 44.0 mm (95% CI 42.4 to 45.6) on radiographs of the hip and 44.7 mm (95% CI 43.5 to 45.9) on CT scans. AP radiographs of the pelvis underestimated femoral offset by 13% when compared with CT (p < 0.001). No difference in mean femoral offset was seen between AP radiographs of the hip and CT (p = 0.191). Our results suggest that femoral offset is significantly underestimated on AP radiographs of the pelvis but can be reliably and accurately assessed on AP radiographs of the hip in patients with primary end-stage hip osteoarthritis. We, therefore, recommend that additional AP radiographs of the hip are obtained routinely for the pre-operative assessment of femoral offset when templating before total hip replacement.

Different culture media affect growth characteristics, surface marker distribution and chondrogenic differentiation of human bone marrow-derived mesenchymal stromal cells

BackgroundBone marrow-derived mesenchymal stromal cells (BM-MSCs) play an important role in modern tissue engineering, while distinct variations of culture media compositions and supplements have been reported. Because MSCs are heterogeneous regarding their regenerative potential and their surface markers, these parameters were compared in four widely used culture media compositions.MethodsMSCs were isolated from bone marrow and expanded in four established cell culture media. MSC yield/1000 MNCs, passage time and growth index were observed. In P4, typical MSC surface markers were analysed by fluorescence cytometry. Additionally, chondrogenic, adipogenic and osteogenic differentiation potential were evaluated.ResultsGrowth index and P0 cell yield varied importantly between the media. The different expansion media had a significant influence on the expression of CD10, CD90, CD105, CD140b CD146 and STRO-1. While no significant differences were observed regarding osteogenic and adipogenic differentiation, chondrogenic differentiation was superior in medium A as reflected by GAG/DNA content.ConclusionsThe choice of expansion medium can have a significant influence on growth, differentiation potential and surface marker expression of mesenchymal stromal cells, which is of fundamental importance for tissue engineering procedures.

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 (P = 0.0336). In both groups, Tregs accumulate more within the SF and SM than concurrently in PB (P < 0.0001). Relative Treg frequencies were comparable in all compartments of RA and OA, but Treg concentration was significantly higher in the SM of RA patients (P = 0.025). 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-).

Mobile-bearing lateral unicompartmental knee replacement with the Oxford domed tibial component

The Oxford mobile-bearing unicompartmental knee replacement (UKR) is an effective and safe treatment for osteoarthritis of the medial compartment. The results in the lateral compartment have been disappointing due to a high early rate of dislocation of the bearing. A series using a newly designed domed tibial component is reported. The first 50 consecutive domed lateral Oxford UKRs in 50 patients with a mean follow-up of three years (2.0 to 4.3) were included. Clinical scores were obtained prospectively and Kaplan-Meier survival analysis was performed for different endpoints. Radiological variables related to the position and alignment of the components were measured. One patient died and none was lost to follow-up. The cumulative incidence of dislocation was 6.2% (95% confidence interval (CI) 2.0 to 17.9) at three years. Survival using revision for any reason and aseptic revision was 94% (95% CI 82 to 98) and 96% (95% CI 85 to 99) at three years, respectively. Outcome scores, visual analogue scale for pain and maximum knee flexion showed a significant improvement (p < 0.001). The mean Oxford knee score was 43 (SD 5.3), the mean Objective American Knee Society score was 91 (SD 13.9) and the mean Functional American Knee Society score was 90 (SD 17.5). The mean maximum flexion was 127° (90° to 145°). Significant elevation of the lateral joint line as measured by the proximal tibial varus angle (p = 0.04) was evident in the dislocation group when compared with the non-dislocation group. Clinical results are excellent and short-term survival has improved when compared with earlier series. The risk of dislocation remains higher using a mobile-bearing UKR in the lateral compartment when compared with the medial compartment. Patients should be informed about this complication. To avoid dislocations, care must be taken not to elevate the lateral joint line.

FGF-2 addition during expansion of human bone marrow-derived stromal cells alters MSC surface marker distribution and chondrogenic differentiation potential.

Although clinical applications using mesenchymal stromal cells (MSCs) are becoming more frequent, procedures for their in vitro culture are far from standardized. Growth factors such as FGF‐2 are frequently added during expansion to improve population growth and differentiation characteristics. However, up to now its influence on surface marker distribution of MSCs has been close to unknown. The purpose of this study was therefore to analyse effects of FGF‐2 supplementation on pre‐selection of MSC subpopulations.

Unicompartmental and bicompartmental knee osteoarthritis show different patterns of mononuclear cell infiltration and cytokine release in the affected joints

It is still controversial which cell types are responsible for synovial inflammation in osteoarthritic (OA) joints. The aim of this study was to quantify the mononuclear cell populations and their cytokines in patients with different knee OA subtypes. Synovial membrane (SM), synovial fluid (SF) and peripheral blood (PB) were harvested from patients with unicompartmental (UC) and bicompartmental (BC) knee OA. Frequencies of mononuclear cells were assessed by flow cytometry in PB and SM. Naive SF samples were analysed for a broad variety of cytokines by multiplex analysis. SM of both groups displayed a distinct mononuclear cell infiltration, with CD14+ macrophages being the major cell population, followed by CD4+ T cells and only small numbers of CD8+ T, CD19+ B and CD16+CD56+ natural killer (NK) cells. Between the two groups, SM of BC OA showed significantly higher amounts of mononuclear cells (135·7 ± 180 versus 805 ± 675 cells/mg, P = 0·0009) and higher CD4+ T cell presence (3·4 ± 4·6 versus 9·1 ± 7·5%, P = 0·0267). SF of BC OA displayed significantly higher concentrations for a number of proinflammatory cytokines [CXCL1, eotaxin, interferon (IFN)‐γ, interleukin (IL)‐7, IL‐8, IL‐9, IL‐12]. UC and BC OA show significant differences in their synovial inflammatory pattern. Whereas in UC OA CD14+ macrophages are the predominant cell population, BC OA has a higher inflammatory profile and seems to be driven by CD14+ macrophages and CD4+ T cells. Inclusion of clinical information into the analysis of cellular and molecular results is pivotal in understanding the pathophysiology of OA.

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.

Engineering hydrophobin DewA to generate surfaces that enhance adhesion of human but not bacterial cells

Hydrophobins are fungal proteins with the ability to form immunologically inert membranes of high stability, properties that makes them attractive candidates for orthopaedic implant coatings. Cell adhesion on the surface of such implants is necessary for better integration with the neighbouring tissue; however, hydrophobin surfaces do not mediate cell adhesion. The aim of this project was therefore to investigate whether the class I hydrophobin DewA from Aspergillus nidulans can be functionalized for use on orthopaedic implant surfaces. DewA variants bearing either one RGD sequence or the laminin globular domain LG3 binding motif were engineered. The surfaces of both variants showed significantly increased adhesion of mesenchymal stem cells (MSCs), osteoblasts, fibroblasts and chondrocytes; in contrast, the insertion of binding motifs RGD and LG3 in DewA did not increase Staphylococcus aureus adhesion to the hydrophobin surfaces. Proliferation of MSCs and their osteogenic, chondrogenic and adipogenic differentiation potential were not affected on these surfaces. The engineered surfaces therefore enhanced MSC adhesion without interfering with their functionality or leading to increased risk of bacterial infection.

Prediction of three-dimensional femoral offset from AP pelvis radiographs in primary hip osteoarthritis.

BACKGROUND In pre-operative planning for total hip arthroplasty (THA), femoral offset (FO) is frequently underestimated on AP pelvis radiographs as a result of inaccurate patient positioning, imprecise magnification, and radiographic beam divergence. The aim of the present study was to evaluate the accuracy and reliability of predicting three-dimensional (3-D) FO from standardised AP pelvis radiographs. METHODS In a retrospective cohort study, pre-operative AP pelvis radiographs, AP hip radiographs and CT scans of a consecutive series of 345 patients (345 hips, 146 males, 199 females, mean age 60 (range: 40-79) years, mean body-mass-index 27 (range: 19-57)kg/m(2)) with primary end-stage hip OA were reviewed. Patients were positioned according to a standardised protocol and all images were calibrated. Using validated custom programmes, FO was measured on corresponding radiographs and CT scans. Measurement reliability was evaluated using intra-class-correlation-coefficients. To predict 3-D FO from AP pelvis measurements and to assess the accuracy compared to CT, the entire cohort was randomly split into subgroups A and B. Gender specific regression equations were derived from group A (245 patients) and the accuracy of prediction was evaluated in group B (100 patients) using Bland-Altman plots. RESULTS In the entire cohort, mean FO was 39.2mm (95%CI: 38.5-40.0mm) on AP pelvis radiographs, 44.1mm (95%CI: 43.4-44.9mm) on AP hip radiographs and 44.6mm (95%CI: 44.0-45.2mm) on CT scans. In group B, we observed no significant difference between gender specific predicted FO (males: 48.0mm, 95%CI: 47.1-48.8mm; females: 42.0mm, 95%CI: 41.1-42.8mm) and FO as measured on CT (males: 47.7mm, 95%CI: 46.1-49.4mm, p=0.689; females: 41.6mm, 95%CI: 40.3-43.0mm, p=0.607). CONCLUSIONS The present study suggests that FO can be accurately and reliably predicted from AP pelvis radiographs in patients with primary end-stage hip osteoarthritis. Our findings support the surgeon in pre-operative templating on AP-pelvis radiographs and may improve offset and limb length restoration in THA without the routine performance of additional radiographs or CT.