Christoph Zilkens

Radiographic and Patient Factors Associated with Pre-Radiographic Osteoarthritis in Hip Dysplasia

BACKGROUND Hip dysplasia leads to abnormal loading of articular cartilage, which results in osteoarthritis. The purpose of this study was to investigate the anatomic and demographic factors associated with the early onset of osteoarthritis in dysplastic hips by utilizing the delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) index as a marker of the disease. METHODS Ninety-six symptomatic dysplastic hips in seventy-four patients were assessed with standard radiographs and a dGEMRIC scan. The lateral center-edge angle of Wiberg, the acetabular index of Tönnis, and the break in the Shenton line were measured on a standing anteroposterior radiograph. Anterior undercoverage was assessed by measuring the anterior center-edge angle on a Lequesne false-profile view. A labral tear was considered to be present when contrast agent was seen through the entire thickness of the labrum on magnetic resonance arthrography. Osteoarthritis was defined as a dGEMRIC value of <390 msec (two standard deviations below the dGEMRIC index in normal hips). RESULTS The mean dGEMRIC index (and standard deviation) for this cohort (473 +/- 104 msec) was significantly lower than that of a morphologically normal hip (570 +/- 90 msec). The anterior center-edge angle, the joint space width, and the presence of a labral tear were all found to be associated with osteoarthritis in the univariate analysis. Multivariate analysis identified age, the anterior center-edge angle, and the presence of a labral tear as independent factors associated with osteoarthritis. A second model was fitted with omission of the anterior center-edge angle because the lateral and anterior center-edge angles were highly correlated and the lateral center-edge angle is a more common clinical measure. This model identified age, the lateral center-edge angle, and the presence of a labral tear as significant independent factors associated with osteoarthritis. CONCLUSIONS As has been demonstrated in previous studies of the hip, this investigation showed osteoarthritis to be associated with increasing age and the severity of dysplasia, as demonstrated both by the Wiberg lateral center-edge angle and the Lequesne anterior center-edge angle. Additionally, we identified a labral tear as being a risk factor for osteoarthritis.

Significance of Nano- and Microtopography for Cell-Surface Interactions in Orthopaedic Implants

Cell-surface interactions play a crucial role for biomaterial application in orthopaedics. It is evident that not only the chemical composition of solid substances influence cellular adherence, migration, proliferation and differentiation but also the surface topography of a biomaterial. The progressive application of nanostructured surfaces in medicine has gained increasing interest to improve the cytocompatibility and osteointegration of orthopaedic implants. Therefore, the understanding of cell-surface interactions is of major interest for these substances. In this review, we elucidate the principle mechanisms of nano- and microscale cell-surface interactions in vitro for different cell types onto typical orthopaedic biomaterials such as titanium (Ti), cobalt-chrome-molybdenum (CoCrMo) alloys, stainless steel (SS), as well as synthetic polymers (UHMWPE, XLPE, PEEK, PLLA). In addition, effects of nano- and microscaled particles and their significance in orthopaedics were reviewed. The significance for the cytocompatibility of nanobiomaterials is discussed critically.

Bridging the gap: bone marrow aspiration concentrate reduces autologous bone grafting in osseous defects.

Although autologous bone grafting represents an effective tool to induce osteogenic regeneration in local bone defects or pseudarthroses, it is associated with significant donor site morbidity and limited by the amount available for grafting. We investigate the potency of bone marrow aspiration concentrate (BMAC) to augment bone grafting and support bone healing. The functional and radiographic outcome of 39 patients with volumetric bone deficiencies treated with BMAC are presented and evaluated in a prospective clinical trial. A collagen sponge (Col) served as scaffold in 12 patients and a bovine hydroxyapatite (HA) was applied in the other 27 individuals. The minimal follow‐up was 6 months. Clinical and radiographic findings were completed by in vitro data. All patients showed new bone formation in radiographs during follow‐up. However, two patients underwent revision surgery due to a lack in bone healing. In contrast to the Col group, the postoperative bone formation appeared earlier in the HA group (HA group: 6.8 weeks vs. Col group 13.6 weeks). Complete bone healing was achieved in the HA group after 17.3 weeks compared to 22.4 weeks in the Col group. The average concentration factor of BMAC was 5.2 (SD 1.3). Flow cytometry confirmed the mesenchymal nature of the cells. Cells from BMAC created earlier and larger colonies of forming units fibroblasts (CFU‐F) compared to cells from bone marrow aspirate. BMAC combined with HA can reduce the time needed for healing of bone defects when compared to BMAC in combination with collagen sponge.

Insufficient stromal support in MDS results from molecular and functional deficits of mesenchymal stromal cells

Ineffective hematopoiesis is a major characteristic of myelodysplastic syndromes (MDS) causing relevant morbidity and mortality. Mesenchymal stromal cells (MSC) have been shown to physiologically support hematopoiesis, but their contribution to the pathogenesis of MDS remains elusive. We show that MSC from patients across all MDS subtypes (n=106) exhibit significantly reduced growth and proliferative capacities accompanied by premature replicative senescence. Osteogenic differentiation was significantly reduced in MDS-derived MSC, indicated by cytochemical stainings and reduced expressions of Osterix and Osteocalcin. This was associated with specific methylation patterns that clearly separated MDS–MSC from healthy controls and showed a strong enrichment for biological processes associated with cellular phenotypes and transcriptional regulation. Furthermore, in MDS–MSC, we detected altered expression of key molecules involved in the interaction with hematopoietic stem and progenitor cells (HSPC), in particular Osteopontin, Jagged1, Kit-ligand and Angiopoietin as well as several chemokines. Functionally, this translated into a significantly diminished ability of MDS-derived MSC to support CD34+ HSPC in long-term culture-initiating cell assays associated with a reduced cell cycle activity. Taken together, our comprehensive analysis shows that MSC from all MDS subtypes are structurally, epigenetically and functionally altered, which leads to impaired stromal support and seems to contribute to deficient hematopoiesis in MDS.

Assessment of osteoarthritis in hips with femoroacetabular impingement using delayed gadolinium enhanced MRI of cartilage

To determine the feasibility of assessing early osteoarthritis (OA) in hips with femoroacetabular impingement (FAI) using delayed Gadolinium enhanced MRI of Cartilage (dGEMRIC).

Rationale for prostaglandin I2 in bone marrow oedema--from theory to application.

IntroductionBone marrow oedema (BME) and avascular osteonecrosis (AVN) are disorders of unclear origin. Although there are numerous operative and non-operative treatments for AVN, pain management in patients with AVN remains challenging. Prostaglandins play an important role in inflammatory responses and cell differentiation. It is thought that prostaglandin I2 ([PGI2] or synonoma prostacyclin) and its analogues promote bone regeneration on a cellular or systemic level. The purpose of this study was to assess the curative and symptomatic efficacy of the prostacyclin analogue iloprost in BME and AVN patients.MethodWe are reporting on 50 patients (117 bones) affected by BME/AVN who were treated with iloprost. Pain levels before, during and 3 and 6 months after iloprost application were evaluated by a visual analogue scale (VAS). The short form(SF)-36 health survey served to judge general health status before and after treatment. Harris Hip Score (HHS) and Knee Society Score (KSS) were performed as functional scores and MRI and X-rays before and 3 and 6 months after iloprost application served as objective parameters for morphological changes of the affected bones.ResultsWe found a significant improvement in pain, functional and radiological outcome in BME and early AVN stages after iloprost application, whereas patients with advanced AVN stages did not benefit from iloprost infusions. Mean pain level decreased from 5.26 (day 0) to 1.63 (6 months) and both HHS and KSS increased during follow-up. Moreover, the SF-36 increased from 353.2 (day 0) to 560.5 points (6 months). We found a significant decrease in BME on MRI scans after iloprost application.ConclusionsIn addition to other drugs, iloprost may be an alternative substance which should be considered in the treatment of BME/AVN-associated pain.

Oxidative stress in secondary osteoarthritis: from cartilage destruction to clinical presentation?

Due to an increasing life expectance, osteoarthritis (OA) is one of the most common chronic diseases. Although strong efforts have been made to regenerate degenerated joint cartilage, OA is a progressive and irreversible disease up to date. Among other factors the dysbalance between free radical burden and cellular scavenging mechanisms defined as oxidative stress is a relevant part of OA pathogenesis. Here, only little data are available about the mediation and interaction between different joint compartments. The article provides a review of the current literature regarding the influence of oxidative stress on cellular aging, senescence and apoptosis in different joint compartments (cartilage, synovial tissue and subchondral bone). Free radical exposure is known to promote cellular senescence and apoptosis. Radical oxygen species (ROS) involvement in inflammation, fibrosis control and pain nociception has been proven. The data from literature indicates a link between free radical burden and OA pathogenesis mediating local tissue reactions between the joint compartments. Hence, oxidative stress is likely not only to promote cartilage destruction but also to be involved in inflammative transformation, promoting the transition from clinically silent cartilage destruction to apparent OA. ROS induced by exogenous factors such as overload, trauma, local intraarticular lesion and consecutive synovial inflammation cause cartilage degradation. In the affected joint, free radicals mediate disease progression. The interrelationship between oxidative stress and OA etiology might provide a novel approach to the comprehension and therefore modification of disease progression and symptom control.

Cell therapy in bone healing disorders

In addition to osteosynthetic stabilizing techniques and autologous bone transplantations, so-called orthobiologics play an increasing role in the treatment of bone healing disorders. Besides the use of various growth factors, more and more new data suggest that cell-based therapies promote local bone regeneration. For ethical and biological reasons, clinical application of progenitor cells on the musculoskeletal system is limited to autologous, postpartum stem cells. Intraoperative one-step treatment with autologous progenitor cells, in particular, delivered promising results in preliminary clinical studies. This article provides an overview of the rationale for, and characteristics of the clinical application of cell-based therapy to treat osseous defects based on a review of existing literature and our own experience with more than 100 patients. Most clinical trials report successful bone regeneration after the application of mixed cell populations from bone marrow. The autologous application of human bone marrow cells which are not expanded ex vivo has medico-legal advantages. However, there is a lack of prospective randomized studies including controls for cell therapy for bone defects. Autologous bone marrow cell therapy seems to be a promising treatment option which may reduce the amount of bone grafting in future.

Delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC), after slipped capital femoral epiphysis

OBJECTIVE The aim of this study was to assess the glycosaminoglycan (GAG) content in hip joint cartilage in mature hips with a history of slipped capital femoral epiphysis (SCFE) using delayed gadolinium-enhanced MRI of cartilage (dGEMRIC). METHODS 28 young-adult subjects (32 hips) with a mean age of 23.8 ± 4.0 years (range: 18.1-30.5 years) who were treated for mild or moderate SCFE in adolescence were included into the study. Hip function and clinical symptoms were evaluated with the Harris hip score (HHS) system at the time of MRI. Plain radiographic evaluation included Tonnis grading, measurement of the minimal joint space width (JSW) and alpha-angle measurement. The alpha-angle values were used to classify three sub-groups: group 1=subjects with normal femoral head-neck offset (alpha-angle <50°), group 2=subjects with mild offset decrease (alpha-angle 50°-60°), and group 3=subjects with severe offset decrease (alpha-angle >60°). RESULTS There was statistically significant difference noted for the T1(Gd) values, lateral and central, between group 1 and group 3 (p-values=0.038 and 0.041). The T1(Gd) values measured within the lateral portion were slightly lower compared with the T1(Gd) values measured within the central portion that was at a statistically significance level (p-value <0.001). HHS, Tonnis grades and JSW revealed no statistically significant difference. CONCLUSION By using dGEMRIC in the mid-term follow-up of SCFE we were able to reveal degenerative changes even in the absence of joint space narrowing that seem to be related to the degree of offset pathology. The dGEMRIC technique may be a potential diagnostic modality in the follow-up evaluation of SCFE.

Diagnostic accuracy of neutrophil‐derived circulating free DNA (cf‐DNA/NETs) for septic arthritis

The release of “neutrophil extracellular traps” (NETs) has been identified as a novel immune response in innate immunity. NETs are composed of neutrophil‐derived circulating free DNA (cf‐DNA) and neutrophil cytoplasm‐derived proteins such as proteases. In this study, we analyzed the putative diagnostic value of synovial cf‐DNA/NETs for identification of septic arthritis. Forty‐two patients with a joint effusion who had undergone arthrocentesis were included. From synovial fluid, cf‐DNA/NETs (j‐cf‐DNA) levels were directly quantified. Diagnostic value of j‐cf‐DNA was compared with white blood cells (WBC), synovial white blood cells (j‐WBC), C‐reactive protein (CRP), j‐IL‐6, j‐TNF alpha, j‐IL‐1 beta, and myeloperoxidase (j‐MPO). Sensitivity, specificity, positive and negative predictive value, as well as ROC‐curves for each parameter were calculated. Synovial fluid cf‐DNA/NETs values from patients with septic arthritis (3,286 ± 386 ng/ml, n = 9) were significantly increased compared to patients with noninfectious joint inflammation (1,040 ± 208 ng/ml, n = 17) or osteoarthritis (278 ± 34 ng/ml, n = 16, p < 0.01). In conjunction with j‐cf‐DNA, j‐IL‐6 and j‐IL‐1 beta were significantly elevated (p < 0.01), but WBC, CRP, and j‐WBC were not. At a cut‐off of 300 ng/ml, j‐cf‐DNA had a sensitivity of 0.89, a specificity of 1.0, a positive predictive value of 1.0, and a negative predictive value of 0.97. Receiver operation curves revealed largest areas under the curve for cf‐DNA/NETs (0.933) and j‐IL‐6 (0.951). cf‐DNA/NETs seem to be a valuable additional marker for the diagnosis of septic arthritis or periprosthetic infections. However, this result should be confirmed in a large clinical trial.