Prognostic value of B-score for predicting joint replacement in the context of osteoarthritis phenotypes: Data from the osteoarthritis initiative.

Objective: Developing new therapies for knee osteoarthritis (KOA) requires improved prediction of disease progression. This study evaluated the prognostic value of clinical clusters and machine-learning derived quantitative 3D bone shape B-score for predicting total and partial knee replacement (KR). Design: This retrospective study used longitudinal data from the Osteoarthritis Initiative. A previous study used patients' clinical profiles to delineate phenotypic clusters. For these clusters, the distribution of B-scores was assessed (employing Tukey's method). The value of both cluster allocation and B-score for KR-prediction was then evaluated using multivariable Cox regression models and Kaplan-Meier curves for time-to-event analyses. The impact of using B-score vs. cluster was evaluated using a likelihood ratio test for the multivariable Cox model; global performances were assessed by concordance statistics (Harrell's C-index) and time dependent receiver operating characteristic (ROC) curves. Results: B-score differed significantly for the individual clinical clusters (p â€‹< â€‹0.001). Overall, 9.4% of participants had a KR over 9 years, with a shorter time to event in clusters with high B-score at baseline. Those clusters were characterized clinically by a high rate of comorbidities and potential signs of inflammation. Both phenotype and B-score independently predicted KR, with better prediction if combined (P â€‹< â€‹0.001). B-score added predictive value in groups with less pain and radiographic severity but limited physical activity. Conclusions: B-scores correlated with phenotypes based on clinical patient profiles. B-score and phenotype independently predicted KR surgery, with higher predictive value if combined. This can be used for patient stratification in drug development and potentially risk prediction in clinical practice.

Pain-phenotyping in osteoarthritis: Current concepts, evidence, and considerations towards a comprehensive framework for assessment and treatment.

Objectives: Pain as central symptom of osteoarthritis (OA) needs to be addressed as part of successful treatment. The assessment of pain as feature of disease or outcome in clinical practice and drug development remains a challenge due to its multidimensionality and the plethora of confounders. This article aims at providing insights into our understanding of OA pain-phenotypes and suggests a framework for systematic and comprehensive assessments. Methods: This narrative review is based on a search of current literature for various combinations of the search terms "pain-phenotype" and "knee OA" and summarizes current knowledge on OA pain-phenotypes, putting OA pain and its assessment into perspective of current research efforts. Results: Pain is a complex phenomenon, not necessarily associated with tissue damage. Various pain-phenotypes have been described in knee OA. Among those, a phenotype with high pain levels not necessarily matching structural changes and a phenotype with low pain levels and impact are relatively consistent. Further subgroups can be differentiated based on patient reported outcome measures, assessments of comorbidities, anxiety and depression, sleep, activity and objective measures such as quantitative sensory testing. Conclusions: The complexity of both OA as disease and pain in OA prompt the definition of a set of variables that facilitate assessments comparable across studies to maximize our understanding of pain, as central concern for the patient.

Periodontal ligament cells as alternative source for cell-based therapy of tendon injuries: in vivo study of full-size Achilles tendon defect in a rat model.

Tendon's natural healing potential is extremely low and inefficient, with significant dysfunction and disability due to hypocellularity and hypovascularity of tendon tissues. The application of stem cells can aid in significantly enhanced repair of tendon rupture; therefore, the main aim of this study is to assess the potential of using periodontal ligament cells (PDL), usually obtained from patients undergoing orthodontic treatment, as a novel cell source for cell-based therapy for tendon injuries in a clinically relevant rat full-size Achilles tendon defect. In addition, the study compares the differences between the healing effects of Achilles tendon-derived cells (AT) versus PDL and, hence, comprises of four experimental groups, native tendon (NT), empty defect (ED), PDL and human AT (hAT). The tendon healing in each group was assessed in the late remodelling phase at 16 weeks after surgery using a combination of methods, including evaluation of gross morphological appearance; various histological and immunohistological stainings; and detailed analyses of cell morphometry. Based on these outcome measures, PDL cell-implanted tendons exhibited not only advanced tissue maturation, less ectopic fibrocartilage formation, more organised collagen fibres, tendon matrix expression corresponding to the final healing stage, and better cell-morphometry parameters when compared with the ED group, but were also very similar to the tendons treated with hAT-derived cells. Taken together, our study clearly demonstrates the feasibility of using PDL cells as a novel cell source for tendon repair and strongly recommends this cell type for the future development of innovative regenerative applications for treatment of different tendon or ligament pathologies.

Value of a coordinated management of osteoporosis via Fracture Liaison Service for the treatment of orthogeriatric patients.

INTRODUCTION: The prevalence of osteoporosis in female patients over 75 years of age is 59.2 %. In Germany ~6.3-7.8 million patients are affected by osteoporosis. In 77 % of german patients osteoporosis is not treated adequately. Even after fragility fractures only 16-21 % of female patients and 3 % of male patients are supplied with a specific osteoporosis therapy. Establishing a Fracture Liaison Services (FLS) is a possible addition to co-management for an efficient treatment of osteoporosis in orthogeriatric patients. MATERIALS AND METHODS: According to a treatment algorithm adapted to the DVO guideline 2014, data of 251 (77 male, 173 female) patients were collected over 3 months. For the assessment specific and standardized questionnaires were used. There was also a basic laboratory testing for osteoporosis done. RESULTS: The average age of female patients was 76.1 years, in male patients 76.6 years. Thirty-seven patients had vertebral fractures, 25 patients proximal humerus fractures, 18 distal radius fractures and a total of 78 proximal femur fractures were recorded. Eighteen percent of the 251 patients have already been treated with a basic and 11 % with a specific osteoporosis medication. Approximately 40 % of the orthogeriatric patients were diagnosed with osteoporosis for the first time in our clinic. Less than 1 % of the patients had a vitamin D level over 40 ng/ml and 32 % had a vitamin D level under 10 ng/ml. Sixty-five percent of the discharged patients received a basic osteoporosis therapy and 25 % an additional specific therapy. DISCUSSION: Due to the demographic development osteoporosis-associated fractures steadily increase. In addition to the surgical treatment of fractures, osteological diagnosis and treatment are essential components of successful treatment and critical to the prevention of further fractures. A combination of orthogeriatric center and fracture liaison service allows a more efficient treatment of osteoporosis by close supervision of orthogeriatric patients by the physicians involved.

In vitro evaluation of novel antimicrobial coatings for surgical sutures using octenidine.

BACKGROUND: Sutures colonized by bacteria represent a challenge in surgery due to their potential to cause surgical site infections. In order to reduce these type of infections antimicrobially coated surgical sutures are currently under development. In this study, we investigated the antimicrobial drug octenidine as a coating agent for surgical sutures. To achieve high antimicrobial efficacy and required biocompatibility for medical devices, we focused on optimizing octenidine coatings based on fatty acids. For this purpose, antimicrobial sutures were prepared with either octenidine-laurate or octenidine-palmitate at 11, 22, and 33 µg/cm drug concentration normalized per length of sutures. Octenidine containing sutures were compared to the commercial triclosan-coated suture Vicryl® Plus. The release of octenidine into aqueous solution was analyzed and long-term antimicrobial efficacy was assessed via agar diffusion tests using Staphylococcus aureus. For determining biocompatibility, cytotoxicity assays (WST-1) were performed using L-929 mouse fibroblasts. RESULTS: In a 7 days elution experiment, octenidine-palmitate coated sutures demonstrated much slower drug release (11 µg/cm: 7%; 22 µg/cm: 5%; 33 µg/cm: 33%) than octenidine-laurate sutures (11 µg/cm: 82%; 22 µg/cm: 88%; 33 µg/cm: 87%). Furthermore sutures at 11 µg/cm drug content were associated with acceptable cytotoxicity according to ISO 10993-5 standard and showed, similar to Vicryl® Plus, relevant efficacy to inhibit surrounding bacterial growth for up to 9 days. CONCLUSIONS: Octenidine coated sutures with a concentration of 11 µg/cm revealed high antimicrobial efficacy and biocompatibility. Due to their delayed release, palmitate carriers should be preferred. Such coatings are candidates for clinical testing in regard to their safety and efficacy.

[Prevalence and management of osteoporosis in trauma surgery. Implementation of national guidelines during inpatient fracture treatment]. / Prävalenz und Management der Osteoporose in der Unfallchirurgie. Umsetzung der DVO-Empfehlungen in der stationären Frakturbehandlung.

BACKGROUND: Osteoporosis-associated fractures represent a risk factor for developing further fragility fractures. Therefore, guideline-oriented osteoporosis intervention is of utmost importance during inpatient fracture treatment. PATIENTS AND METHODS: Women >50 years and men >60 years with fractures of the lumbar or thoracic spine, proximal femur, proximal humerus and distal radius were included in a prospective study. We analyzed the initiation of diagnosis and treatment of osteoporosis during the inpatient stay. RESULTS: A total of 455 patients were included and bone mineral density measurement (DXA) was carried out in 65.9 %. Women underwent DXA in 69.5 % and men significantly less frequently in 52.1 %. Osteoporosis was diagnosed in 56.6 %, where women were affected in 56.2 % and men in 59 % of cases. In 83.8 % osteoporosis had been previously unknown. Treatment according to the guidelines of the Organisation of German Scientific Osteology-related Societies (DVO) was initiated in 86.7 % and 77.1 % of women >70 years and men >80 years required anti-resorptive treatment after DXA. CONCLUSIONS: The majority of elderly patients with fractures also suffer from osteoporosis, independent of gender. Even nowadays, osteoporosis is predominantly not diagnosed until the incidence of a fracture. Therefore, the trauma surgeon is in a key position to initiate diagnosis and treatment of osteoporosis.

[Osteoid osteoma of the talus: a rare cause for pain in the ankle joint]. / Das Osteoidosteom des Talus: Eine seltene Ursache für Beschwerden des oberen Sprunggelenks.

Osteoid osteomas are typically located in the femur and tibia and are mostly easy to diagnose based on patient age, the clinical signs and plain radiographs. In contrast, the diagnosis of osteoid osteomas of the foot is often delayed because of the atypical presentation. We report the case of a 24-year-old patient with persisting pain in the ankle joint over 8 years due to an osteoid osteoma of the talus neck.

Comparison of tenocytes and mesenchymal stem cells seeded on biodegradable scaffolds in a full-size tendon defect model.

In order to investigate cell-based tendon regeneration, a tendon rupture was simulated by utilizing a critical full-size model in female rat achilles tendons. For bridging the defect, polyglycol acid (PGA) and collagen type I scaffolds were used and fixed with a frame suture to ensure postoperatively a functional continuity. Scaffolds were seeded with mesenchymal stem cells (MSC) or tenocytes derived from male animals, while control groups were left without cells. After a healing period of 16 weeks, biomechanical, PCR, histologic, and electron microscopic analyses of the regenerates were performed. Genomic PCR for male-specific gene was used to detect transplanted cells in the regenerates. After 16 weeks, central ossification and tendon-like tissue in the superficial tendon layers were observed in all study groups. Biomechanical test showed that samples loaded with tenocytes had significantly better failure strength/cross-section ratio (P < 0.01) compared to MSC and the control groups whereas maximum failure strength was similar in all groups. Thus, we concluded that the application of tenocytes improves the outcome in this model concerning the grade of ossification and the mechanical properties in comparison to the use of MSC or just scaffold materials.

Porosity and mechanically optimized PLGA based in situ hardening systems.

Goal of the present study was to develop and to characterize in situ-hardening, porous PLGA-based systems for their future application as bone grafting materials. Therefore, we investigated the precipitation behavior of formulations containing PLGA and a water-miscible solvent, DMSO, PEG 400, and NMP. To increase porosity, a pore forming agent (NaCMC) was added and to enhance mechanical properties of the system, an inorganic filler (α-TCP) was incorporated. The behavior upon contact with water and the influence of the prior addition of aqueous media on the morphology of the corresponding hardened implants were investigated. We proved cell-compatibility by live/dead assays for the hardened porous polymer/ceramic-composite scaffolds. The IsHS formulations can therefore be used to manufacture hardened scaffolds ex vivo by using molds with the desired shape and size. Cells were further successfully incorporated into the IsHS by precultivating the cells on the α-TCP-powder prior to their admixing to the formulation. However, cell viability could not be maintained due to toxicity of the tested solvents. But, the results demonstrate that in vivo cells should well penetrate, adhere, and proliferate in the hardened scaffolds. Consequently, we consider the in situ hardening system being an excellent candidate as a filling material for non-weight-bearing orthopedic indications, as the resulting properties of the hardened implant fulfill indication-specific needs like mechanical stability, elasticity, and porosity.

[Alterations of cell phenotype in Dupuytren's disease--an in vitro analysis]. / Veränderung des Zell-Phänotyps durch Morbus Dupuytren--eine in-vitro-Analyse.

INTRODUCTION: Despite its potential complications, partial aponeurectomy still is the mainstay of treatment whenever it comes to significant contracture in Dupuytren's disease. With the goal in mind to identify new therapeutic strategies we isolated and characterised cells from healthy palmar aponeurosis (Kon) and compared them to cells isolated from palmar aponeurosis of patients with a primary manifestation of Dupuytren's disease (PrimDup) as well as from patients with recurrent Dupuytren's disease (RezDup). As cells from palmar aponeurosis from patients with Dupuytren's disease share characteristics with stem cells, such as the ability to differentiate into other cell types, we analysed the stemness, morphology and integrin receptor profiles of the cells. MATERIALS AND METHODS: A total of 15 Dupuytren samples were collected from regular partial aponeurectomy procedures. From these, 3 donors without extrinsic risk factors were selected per group (RezDup, PrimDup). Cells were isolated and expanded under standard cell culture conditions. Cells from healthy patients served as control (Kon). Growth curves were produced. Cells were subjected to osteogenic and adipogenic differentiation using standard protocols. Semiquantitative PCR analysis of the integrins α2, ß3, ß5 and fibronectin was performed. RESULTS: PrimDup cells proliferated significantly faster than control cells, which in turn proliferated faster than RezDup cells. Both PrimDup and control cells went into senescence after approximately 40 days whereas RezDup cells proliferated over the entire period of 100 days. Osteogenic and adipogenic differentiation was best in cells derived from Dupuytren patients while Kon cells differentiated poorly. PCR analysis revealed that fibronectin-binding integrins ß3 and ß5 are upregulated in Dupuytren's disease. CONCLUSIONS: PrimDup cells grow faster than the other cell types suggesting that their growth regulation may be altered. The fact that RezDup cells do not reach senescence over 100 days in culture indicates that senescence regulating factors may be altered. As cells from Dupuytren patients differentiate better along the osteogenic and adipogenic lineages, they probably possess a higher level of stemness. Their modified integrin profile may be a key to future therapies.

Residual transglutaminase in collagen - effects, detection, quantification, and removal.

In the present study, we developed an enzyme-linked immunosorbent assay (ELISA) for microbial transglutaminase (mTG) from Streptomyces mobaraensis to overcome the lack of a quantification method for mTG. We further performed a detailed follow-on-analysis of insoluble porcine collagen type I enzymatically modified with mTG primarily focusing on residuals of mTG. Repeated washing (4 ×) reduced mTG-levels in the washing fluids but did not quantitatively remove mTG from the material (p < 0.000001). Substantial amounts of up to 40% of the enzyme utilized in the crosslinking mixture remained associated with the modified collagen. Binding was non-covalent as could be demonstrated by Western blot analysis. Acidic and alkaline dialysis of mTG treated collagen material enabled complete removal the enzyme. Treatment with guanidinium chloride, urea, or sodium chloride was less effective in reducing the mTG content.

Integrins α2ß1 and α11ß1 regulate the survival of mesenchymal stem cells on collagen I.

Although mesenchymal stem cells (MSCs) are the natural source for bone regeneration, the exact mechanisms governing MSC crosstalk with collagen I have not yet been uncovered. Cell adhesion to collagen I is mostly mediated by three integrin receptors - α1ß1, α2ß1 and α11ß1. Using human MSC (hMSC), we show that α11 subunit exhibited the highest basal expression levels but on osteogenic stimulation, both α2 and α11 integrins were significantly upregulated. To elucidate the possible roles of collagen-binding integrins, we applied short hairpin RNA (shRNA)-mediated knockdown in hMSC and found that α2 or α11 deficiency, but not α1, results in a tremendous reduction of hMSC numbers owing to mitochondrial leakage accompanied by Bcl-2-associated X protein upregulation. In order to clarify the signaling conveyed by the collagen-binding integrins in hMSC, we analyzed the activation of focal adhesion kinase, extracellular signal-regulated protein kinase and serine/threonine protein kinase B (PKB/Akt) kinases and detected significantly reduced Akt phosphorylation only in α2- and α11-shRNA hMSC. Finally, experiments with hMSC from osteoporotic patients revealed a significant downregulation of α2 integrin concomitant with an augmented mitochondrial permeability. In conclusion, our study describes for the first time that disturbance of α2ß1- or α11ß1-mediated interactions to collagen I results in the cell death of MSCs and urges for further investigations examining the impact of MSCs in bone conditions with abnormal collagen I.

Inhibition of metastasis-associated gene 1 expression affects proliferation and osteogenic differentiation of immortalized human mesenchymal stem cells.

OBJECTIVES: MTA1 is known to be responsible for independent nucleosome remodelling and deacetylase complexes with ability to regulate divergent cellular pathways. However, additional biological functions have, up to now, remained largely unexplored. The present study was initiated to investigate involvement of MTA1 in osteogenic differentiation of immortalized human mesenchymal stem cells (MSCs). MATERIALS AND METHODS: MSCs were examined for expression of MTA1 and stably transfected clones expressing shRNA to MTA1 were generated. Cells were grown under osteogenic and non-osteogenic conditions. Effects of silencing on cell proliferation, calcium deposition and alkaline phosphatase (ALP) activity were studied. mRNA expression of bone sialoprotein (BSP), osteopontin (OSP), runt-related transcription factor 2 (Runx2), osteocalcin (OC), collagen type I (Col1A) and ALP were analysed. RESULTS: Transfected cells showed reduction in proliferation and significant increase in calcium deposition and expression of osteogenic marker genes, BSP, OSP, Runx2, OC and Col1A, when they were grown under osteogenic conditions. Under non-osteogenic conditions, expression of BSP and OSP were also markedly upregulated, whereas expression of osteogenic marker genes, Runx2, OC and Col1A, was almost unaffected. Expression of ALP was slightly suppressed under non-osteogenic conditions but significantly increased under osteogenic differentiation conditions, as assessed by enzyme activity and mRNA expression assays. CONCLUSIONS: Our data collectively suggest that endogenously produced MTA1 constrains osteogenic differentiation of MSCs and that targeting of this molecule may provide a novel strategy for enhancing bone regeneration.

Establishment of immortalized periodontal ligament progenitor cell line and its behavioural analysis on smooth and rough titanium surface.

Periodontal ligament (PDL) can be obtained from patients undergoing orthodontic treatment. PDL contains progenitor cells that can be expanded and differentiated towards several mesenchymal lineages in vitro. Furthermore, PDL-derived cells have been shown to generate bone- and PDL-like structures in vivo. Thus, PDL cells, combined with suitable biomaterials, represent a promising tool for periodontitis-related research and PDL engineering. Here, a new PDL cell line using lentiviral gene transfer of human telomerase reverse transcriptase (hTERT) was created. HTERT-expressing PDL cells showed similar morphology and population doubling time but an extended lifespan compared to the primary cells. In addition, PDL-hTERT cells expressed several characteristic genes and upon osteogenic stimulation produced a calcified matrix in vitro. When cultivated on two topographically different titanium scaffolds (MA and SLA), PDL-hTERT cells exhibited augmented spreading, survival and differentiation on smooth (MA) compared to rough (SLA) surfaces. These findings differ from previously reported osteoblast behaviour, but they are in agreement with the behaviour of chondrocytes and gingival fibroblasts, suggesting a very cell type-specific response to different surface textures. In summary, we report the testing of titanium biomaterials using a new PDL-hTERT cell line and propose this cell line as a useful model system for periodontitis research and development of novel strategies for PDL engineering.

[Bone substitutes]. / Knochenersatzmaterialien.

Bone substitutes are used to supplement or substitute autogenous transplantation of cancellous bone. These materials should provide a scaffold structure and support bone healing alone or in combination with other substances. In trauma surgery the indication for use of bone substitutes lies mostly in filling of small metaphyseal cancellous bone defects with high vascularization following fracture. In comparison to transplantation of cancellous bone, the advantages of bone substitutes are sufficient availability without additional donor site morbidity. Moreover, biomaterials can be stored, also ensuring ready availability. This educational article gives an overview of bone substitutes currently in clinical use.

Tissue attachment strength and adhesion formation of intraabdominal fixed meshes with cyanoacrylat glues.

OBJECTIVE: The aim of this study was to evaluate the technique of prosthetic mesh fixation in laparoscopic intraperitoneal incisional and ventral hernia repair using cyanoacrylat glue (Glubran GEM, Viareggio, Italy) in comparison with fixation methods using spiral tacks (Protack 5mm, Tyco) or transabdominal Prolene 4/0 sutures respectively. METHOD: Through a midline laparotomy 3 pieces (3 x 3cm) of mesh (n = 60) where fixed onto the intact peritoneum on either side of a midline laparotomy in 10 New Zealand White rabbits. Two types of meshes where compared: ePTFE meshes (Gore-Tex Dual Mesh W.L. Gore and Associates, Inc. Medical Products Division, Flagstaff, Arizona, USA) and polypropylene/ polyvinylfluorid meshes (Dyna Mesh - IPOM P.J. Dahlhausen and Co. GmbH, Germany). All animals were killed after 12 weeks. Upon scoring of the adhesions the prosthetic materials were excised en bloc with the anterior abdominal wall for tensile strength analysis and histologic evaluation. RESULTS: In contrast to ePTFE meshes fixed with cyanoacrylat glue, PP meshes fixed with transabdominal sutures as well as with spiral tacks showed the highest percentage and tenacity of adhesions (p<0.033). Independent of the method of fixation, ePTFE meshes revealed a significantly higher shrinkage than PP prosthesis (41% vs 17% related to original mesh surface; p<0.033). The strength of the mesh incorporation was significantly higher in PP meshes (p<0.033). Fixation of PP meshes with cyanoacrylat glue showed an equivalent tensile strength as ePTFE meshes fixed with spiral tacks (6.6 +/- 2.7 N vs 6.6 +/- 3.1N). CONCLUSION: In this rabbit model, intraabdominal fixation of PP composite meshes with cyanoacrylat glue was equivalent to ePTFE mesh fixation with spiral tacks concerning tensile strength analysis. Adhesions between mesh and abdominal wall were found more frequently after PP fixation. In contrast, mesh shrinkage was more evident after ePTFE mesh implantation.

Diagnosis of osteoporosis with vitamin k as a new biochemical marker.

Osteoporosis is a metabolic bone disease characterized by reduced bone quality and quantity. As a consequence, patients are at risk for fractures, subsequent immobility, and higher mortality especially among elder patients. Because of the high incidence of complications and the associated financial burden for the health system, new parameters for diagnostic and therapeutic purposes are urgently needed. In this regard, research focused on vitamin K as a biochemical bone marker has provided promising results. Vitamin K represents an important enzyme-cofactor for the posttranslational modification and activation of several proteins involved in bone metabolism. Vitamin K has been proven to be a valuable diagnostic as well as therapeutic parameter especially in osteoporosis. Patients with osteoporosis have been shown to have decreased levels of vitamin K. Further, regular intake of vitamin K may increase bone mineral density (BMD), thereby lowering the fracture risk. Yet vitamin K alone may not sufficiently indicate the mineral status of the bone. However, the usefulness of a combination of several biochemical bone markers as improved surrogate markers of bone metabolism has been shown recently. Therefore, this review will focus on the significance and importance of vitamin K for bone metabolism. Beyond this, aspects on the current and prospective use of vitamin K as well as other newly developed biochemical bone markers will be discussed.