Markus Rickert

A growth and differentiation factor-5 (GDF-5)-coated suture stimulates tendon healing in an Achilles tendon model in rats.

Growth and differentiation factor-5 (GDF-5) is essential for normal skeletal development and induces tendon-and ligament-like structures at ectopic sites. Therefore, we investigated the influence of a GDF-5-coated suture on the healing Achilles tendon in rats. The right Achilles tendon in 80 rats was transected and sutured with an absorbable polyglactin suture. Animals were randomized to an uncoated-suture control and a GDF-5-coated suture group. At 1, 2, 4 and 8 weeks after surgery the repair tissue was evaluated biomechanically and histologically. Biomechanical testing revealed significantly thicker tendons, which were stiffer at 1, 2, and 4 weeks, in the experimental group than in the control group. The maximum tensile strength was significantly increased at 2 weeks after surgery. Histologically we found cartilage-like cell nests 4 weeks after tendon repair, which were positive for type II collagen. In conclusion, local growth factor delivery by a coated suture material showed a promising beneficial effect on tendon repair. The appearance of cartilage-like structures may demonstrate the chondroinductive capacity of GDF-5, which in these circumstances, however, might be overcome by modifications of the GDF-5 dose and/or the suture material.

Influence of the design of the prosthesis on the outcome after hemiarthroplasty of the shoulder in displaced fractures of the head of the humerus

We reviewed 39 patients with displaced three- and four-part fractures of the humerus. In 21 patients (group A) we had used an anatomical prosthesis for the humeral head and in 18 (group B) an implant designed for fractures. When followed up at a mean of 29.3 months after surgery the overall Constant score was 51.9 points; in group A it was 51.5 and in group B 52.4 points. The subjective satisfaction of the patients was assessed using a numerical rating scale and was similar in both groups. In group A complete healing of the tuberosities was found in 29% and 50% in group B. Partial integration was seen in 29% of group A and in only one patient in group B, while resorption was noted in 43% of group A and 44% of group B. The functional outcome was significantly better in patients with complete or partial healing of the tuberosities (p=0.022). The specific trauma prosthesis did not lead to better healing of the tuberosities. The difference in clinical outcome obtained by the two designs did not reach statistical significance.

Total shoulder replacement in young and middle-aged patients with glenohumeral osteoarthritis

Our aim in this prospective study was to evaluate the outcome of total shoulder replacement in the treatment of young and middle-aged active patients with primary glenohumeral osteoarthritis. We reviewed 21 patients (21 shoulders) with a mean age of 55 years (37 to 60). The mean follow-up was seven years (5 to 9). The same anatomical, third-generation, cemented implant had been used in all patients. All the patients were evaluated radiologically and clinically using the Constant and Murley score. No patients required revision. In one a tear of the supraspinatus tendon occurred. Overall, 20 patients (95%) were either very satisfied (n = 18) or satisfied (n = 2) with the outcome. Significant differences (p < 0.0001) were found for all categories of the Constant and Murley score pre- and post-operatively. The mean Constant and Murley score increased from 24.1 points (10 to 45) to 64.5 points (39 to 93), and the relative score from 30.4% (11% to 50%) to 83% (54% to 116%). No clinical or radiological signs of loosening of the implant were seen. For young and middle-aged patients with osteoarthritis, third-generation total shoulder replacement is a viable method of treatment with a low rate of complications and excellent results in the mid-term.

Adenovirus-Mediated Gene Transfer of Growth and Differentiation Factor-5 into Tenocytes and the Healing Rat Achilles Tendon

Growth and differentiation factor-5 (GDF-5) is known to induce tendon tissue and stimulate tendon healing. The hypothesis was that adenoviral GDF-5 transfer leads to transitory transgene expression and improves Achilles tendon healing. In vitro experiments were first performed with rat tenocytes. Transgene expression was evaluated by RT-PCR, Western blotting and GDF-5-ELISA. In vivo virus dosage and transgene expression were examined by a marker gene transfer (LacZ and luciferase). In the main experiment in 131 rats, adenovirus particles (3× 1010) were injected into transected Achilles tendons. The time course of GDF-5 mRNA expression was assessed by real-time RT-PCR. Histology and biomechanical testing were used to evaluate tendon healing and tensile strength. In vitro GDF-5 was secreted with a maximum after 2 weeks (330 ng GDF-5/106 cells per 24 hr). In vivo GDF-5 transgene expression showed a maximum at 4 weeks. At 8 weeks, GDF-5 specimens were thicker (p < 0.05) with a trend to higher strength (p = 0,064). Histology showed greater cartilage formation in type II collagen stains than in controls. Injection of adenovirus particles successfully can deliver the GDF-5 gene in healing tendons and leads to thicker tendon regenerates after 8 weeks. This technique might become a new approach for nonsurgical treatment of tendon injuries.

Mid-term survivorship analysis of a shoulder replacement with a keeled glenoid and a modern cementing technique

We have investigated the mid-term outcome of total shoulder replacement using a keeled cemented glenoid component and a modern cementing technique with regard to the causes of failure and loosening of the components. Between 1997 and 2003 we performed 96 total shoulder replacements on 88 patients, 24 men and 64 women with a mean age of 69.7 years (31 to 82). The minimum follow-up was five years and at the time of review 87 shoulders (77 patients) were examined at a mean follow-up of 89.1 months (60 to 127). Cumulative survival curves were generated with re-operations (accomplished and planned), survivorship of the proshesis, loosening of the glenoid (defined as tilt > 5 degrees or subsidence > 5 mm), the presence of radiolucent lines and a Constant score of < 30 as the endpoints. There were two re-operations not involving revision of the implants and the survival rate of the prosthesis was 100.0% for the follow-up period, with an absolute Constant score of > 30 as the endpoint the survival rate was 98%. Radiological glenoid loosening was 9% after five years, and 33% after nine years. There was an incidence of 8% of radiolucent lines in more than three of six zones in the immediate post-operative period, of 37.0% after the first year which increased to 87.0% after nine years. There was no correlation between the score of Boileau and the total Constant score at the latest follow-up, but there was correlation between glenoid loosening and pain (p = 0.001). We found that total shoulder replacement had an excellent mid-term survivorship and clinical outcome. The surgical and cementing techniques were related to the decrease in radiolucent lines around the glenoid compared with earlier studies. One concern, however, was the fact that radiolucent lines increased over time and there was a rate of glenoid loosening of 9% after five years and 33% after nine years. This suggests that the design of the glenoid component, and the implantation and cementing techniques may need further improvement.

Effects of platelet-rich plasma (PRP) on the healing of Achilles tendons of rats

Platelet‐rich plasma (PRP) contains growth factors involved in the tissular healing process. The aim of the study was to determine if an injection of PRP could improve the healing of sectioned Achilles tendons of rats. After surgery, rats received an injection of PRP (n = 60) or a physiological solution (n = 60) in situ. After 5, 15, and 30 days, 20 rats of both groups were euthanized and 15 collected tendons were submitted to a biomechanical test using cryo‐jaws before performing transcriptomic analyses. Histological and biochemical analyses were performed on the five remaining tendons in each group. Tendons in the PRP group were more resistant to rupture at 15 and 30 days. The mechanical stress was significantly increased in tendons of the PRP group at day 30. Histological analysis showed a precocious deposition of fibrillar collagen at day 5 confirmed by a biochemical measurement. The expression of tenomodulin was significantly higher at day 5. The messenger RNA levels of type III collagen, matrix metalloproteinases 2, 3, and 9, were similar in the two groups at all time points, whereas type I collagen was significantly increased at day 30 in the PRP group. In conclusion, an injection of PRP in sectioned rat Achilles tendon influences the early phase of tendon healing and results in an ultimately stronger mechanical resistance.

Longitudinal observational study of total shoulder replacements with cement: fifteen to twenty-year follow-up.

BACKGROUND There is little information about the long-term longitudinal outcomes of total shoulder arthroplasty. Moreover, long-term data on a single shoulder replacement system are lacking. The aim of this study was to analyze, at different time points during a follow-up period of fifteen to twenty years, the clinical and radiographic outcomes of patients treated with a third-generation total shoulder arthroplasty. METHODS Sixty-three total shoulder arthroplasties were performed in fifty-eight patients. Two patients were lost to follow-up, and sixteen patients died during the follow-up period, leaving a cohort of forty-five total shoulder arthroplasties in forty patients with a mean age of sixty-four years. Follow-up examinations were carried out at six months, one year, two years, three to four years, five to eight years, nine to fourteen years, and fifteen years or more. Preoperatively and at each follow-up visit, the Constant score as well as shoulder flexion and external rotation were assessed. Radiographs were analyzed for loosening and migration of the components at all time points. RESULTS There was a substantial improvement of all clinical parameters from baseline to the latest follow-up evaluation. Clinical results reached a plateau at one year, remained stable without substantial worsening for eight years, and then remained as good as the six-month results until fifteen years postoperatively. Compared with the outcomes at the six-month follow-up examination, the results were worse beyond fifteen years. The clinical outcome was not influenced by sex, age, hand dominance, glenoid morphology, glenoid loosening, or upward migration of the humeral head. Thirty-three (73%) of the forty-five shoulders had radiographic evidence of glenoid loosening at the time of final follow-up. Fourteen shoulders (31%) were revised: a soft-tissue revision was performed in one of them, and implant revision was necessary in thirteen. CONCLUSIONS Although there is a significant and longitudinal improvement in shoulder function and pain relief after total shoulder replacement, long-term follow-up of fifteen to twenty years demonstrated a high revision rate in this cohort.

A Lipidomic Study of Phospholipid Classes and Species in Human Synovial Fluid

OBJECTIVE Membrane phospholipid species contribute to boundary lubrication that is provided by synovial fluid (SF). Altered levels of lubricants can be associated with increased friction, leading to articular cartilage damage. This study was undertaken to determine whether the composition of phospholipid species is altered in diseases of human knee joints. METHODS The study was performed using SF from unaffected controls and patients with early osteoarthritis (OA), late OA, or rheumatoid arthritis (RA). Lipids were extracted from cell- and vesicle-free SF from 9 control donors postmortem and from 17 patients with early OA, 13 patients with late OA, and 18 patients with RA. Phospholipid species were quantified by electrospray ionization tandem mass spectrometry. RESULTS We conducted lipidomic analysis to provide the first detailed overview of phospholipid species in human SF. We identified 130 lipid species belonging to 8 lipid classes (phosphatidylcholine, lysophosphatidylcholine, phosphatidylethanolamine, plasmalogens, phosphatidylserine, phosphatidylglycerol, sphingomyelin, and ceramide). Compared to SF from controls, SF from patients with early OA and those with late OA had higher levels of most phospholipid species. Moreover, the concentrations of 64 and 27 phospholipids differed between RA and early OA SF and between RA and late OA SF, respectively. Also, the levels of 66 phospholipid species were altered in early OA versus late OA. CONCLUSION Our data indicate disease- and stage-dependent differences in the relative composition and levels of phospholipid species in human SF. Such alterations might affect articular joint lubrication. Because certain phospholipids scavenge reactive oxygen species (ROS) and are pro- or antiinflammatory, any altered phospholipid level might influence ROS-scavenging activity of SF and the inflammatory status of joints. Thus, phospholipids may be associated with the pathogenesis of OA.

Rapid regulation of collagen but not metalloproteinase 1, 3, 13, 14 and tissue inhibitor of metalloproteinase 1, 2, 3 expression in response to mechanical loading of cartilage explants in vitro.

This study analyzes the molecular response of articular chondrocytes to short-term mechanical loading with a special focus on gene expression of molecules relevant for matrix turnover. Porcine cartilage explants were exposed to static and dynamic unconfined compression and viability of chondrocytes was assessed to define physiologic loading conditions. Cell death in the superficial layer correlated with mechanical loading and occurred at peak stresses >or=6 MPa and a cartilage compression above 45%. Chondrocytes in native cartilage matrix responded to dynamic loading by rapid and highly specific suppression of collagen expression. mRNA levels dropped 11-fold (collagen 2; 6 MPa, P=0.009) or 14-fold (collagen 1; 3 and 6 MPa, P=0.009) while levels of aggrecan, tenascin-c, matrix metalloproteinases (MMP1, 3, 13, 14), and their inhibitors (TIMP1-3) did not change significantly. Thus, dynamic mechanical loading rapidly shifted the balance between collagen and aggrecan/tenascin/MMP/TIMP expression. A better knowledge of the chondrocyte response to mechanical stress may improve our understanding of mechanically induced osteoarthrits.

Adiponectin isoforms: a potential therapeutic target in rheumatoid arthritis?

Objectives Several clinical studies have suggested the adipocytokine adiponectin is involved in the progression of rheumatoid arthritis (RA). From this point of view, adiponectin might present a new therapeutic target. However, as adiponectin also exerts beneficial effects in the human organism, a strategy that would allow its detrimental effects to be abolished while maintaining the positive effects would be highly favourable. To elucidate such a strategy, the authors analysed whether the different adiponectin isoforms induce diverging effects, especially with regard to rheumatoid arthritis synovial fibroblasts (RASF), a central cell type in RA pathogenesis capable of invading into and destroying cartilage. Methods Affymetrix microarrays were used to screen for changes in gene expression of RASF. Messenger RNA levels were quantified by real-time PCR, protein levels by immunoassay. The migration of RASF and primary human lymphocytes was analysed using a two-chamber migration assay. Results In RASF, the individual adiponectin isoforms induced numerous genes/proteins relevant in RA pathogenesis to clearly different extents. In general, the most potent isoforms were the high molecular weight/middle molecular weight isoforms and the globular isoform, while the least potent isoform was the adiponectin trimer. The chemokines secreted by RASF upon adiponectin stimulation resulted in an increased migration of RASF and lymphocytes. Conclusion The results clearly suggest a pro-inflammatory and joint-destructive role of all adiponectin isoforms in RA pathophysiology, indicating that in chronic inflammatory joint diseases the detrimental effects outweigh the beneficial effects of adiponectin.