Bioactive functional scaffolds are essential for support of cell-based strategies to improve bone regeneration. Adipose-tissue-derived-stromal-cells (ASC) are more accessible multipotent cells with faster proliferation than bone-marrow-derived-stromal-cells (BMSC) having potential to replace BMSC for therapeutic stimulation of bone-defect healing. Their osteogenic potential is, however lower compared to BMSC, a deficit that may be overcome in growth factor-rich orthotopic bone defects with enhanced bone-conductive scaffolds. Objective of this study was to compare the therapeutic potency of human ASC and BMSC for bone regeneration on a novel nanoparticulate β-TCP/collagen-carrier (β-TNC). Cytotoxicity of β-TCP nanoparticles and multilineage differentiation of cells were characterized in vitro. Cell-seeded β-TNC versus cell-free controls were implanted into 4 mm calvarial bone-defects in immunodeficient mice and bone healing was quantified by µCT at 4 and 8 weeks. Tissue-quality and cell-origin were assessed by histology. β-TNC was non-toxic, radiolucent and biocompatible, lent excellent support for human cell persistence and allowed formation of human bone tissue by BMSC but not ASC. Opposite to BMSC, ASC-grafting significantly inhibited calvarial bone healing compared to controls. Bone formation progressed significantly from 4 to 8 weeks only in BMSC and controls yielding 5.6-fold more mineralized tissue in BMSC versus ASC-treated defects. Conclusively, β-TNC was simple to generate, biocompatible, osteoconductive, and stimulated osteogenicity of BMSC to enhance calvarial defect healing while ASC had negative effects. Thus, an orthotopic environment and β-TNC could not compensate for cell-autonomous deficits of ASC which should systematically be considered when choosing the right cell source for tissue engineering-based stimulation of bone regeneration.

Dynamic compressive loading of cartilage can support extracellular matrix (ECM) synthesis whereas abnormal loading such as disuse, static loading or altered joint biomechanics can disrupt the ECM, suppress the biosynthetic activity of chondrocytes and lead to osteoarthritis. Interactions with the pericellular matrix are believed to play a critical role in the response of chondrocytes to mechanical signals. Loading of intact cartilage explants can stimulate proteoglycan synthesis immediately while the response of chondrocytes in tissue engineering constructs dependent on the day of culture. In order to effectively utilize mechanical signals in the clinic as a non-drug-based intervention to improve cartilage regeneration after surgical treatment, it is essential to understand how ECM accumulation influences the loading response. This study explored how construct maturity affects regulation of ECM synthesis of chondrocytes exposed to dynamic loading and unraveled the molecular correlates of this response.

Human chondrocytes were expanded to passage 2, seeded into collagen scaffolds and cultured for 3, 21, or 35 days before exposure to a single loading episode. Dynamic compression was applied at 25% strain, 1 Hz, in 9 × 10 minute-intervals over 3h. Gene expression and protein alterations were characterized by qPCR and Western blotting. Proteoglycan and collagen synthesis were determined by radiolabel-incorporation over 24 hours.

Maturation of constructs during culture significantly elevated ECM deposition according to histology and GAG/DNA content and chondrocytes redifferentiated as evident from raising COL2A1 and ACAN expression. Loading of d3 constructs significantly reduced proteoglycan synthesis and ACAN expression compared to controls while the identical loading episode stimulated GAG production significantly (1.45-fold, p=0.016) in day 35 constructs. Only in mature constructs, pERK1/2 and its immediate response gene FOS were stimulated by loading. Also, SOX9 protein increased after loading only in d21 and d35 but not in d3 constructs. Interestingly, levels of phosphorylated Smad 1/5/9 protein declined during construct maturation, but no evidence was obtained for load-induced changes in pSmad 1/5/9 although BMP2 and BMP6 expression were stimulated by loading. Selected MAPK-, calcium-, Wnt- and Notch-responsive genes raised significantly independent of construct maturity albeit with a generally weaker amplitude in d3 constructs.

In conclusion, construct maturity determined whether cells showed an anabolic or catabolic response to the same loading episode and this was apparently determined by a differential SOX9 and pERK signaling response on a background of high versus low total pSmad1/5/9 protein levels. Next step is to use signaling inhibitors to investigate a causal relationship between Smad levels and a beneficial loading response in order to design cartilage replacement tissue for an optimal mechanical response for in vivo applications.

Objective

Early cell loss of up to 50% is common to in vitro chondrogenesis of mesenchymal stromal cells (MSC) and stimulation of cell proliferation could compensate for this unwanted effect and improve efficacy and tissue yield for cartilage tissue engineering. We recently demonstrated that proliferation is an essential requirement for successful chondrogenesis of MSC, however, how it is regulated is still completely unknown. We therefore aimed to identify signaling pathways involved in the regulation of proliferation during in vitro chondrogenesis and investigated, whether activation of relevant pathways could stimulate proliferation.

Objective

In order to effectively utilize mechanical signals in the clinic as a non-drug-based intervention to improve cartilage defect regeneration after surgical treatment, it is essential to identify crucial components of the cellular response that are typical to the anabolic process. The mechanisms behind the effect of mechanical stimulation are, however, not fully understood and the signaling pathways involved in the anabolic response of chondrocytes to mechano-transduction are not well described. Therefore, a genome-wide identification of mechano-regulated genes and candidate pathways in human chondrocytes subjected to a single anabolic loading episode was performed in this study and time evolution and re-inducibility of the response was characterized.

While mesenchymal stromal cells (MSCs) are a very attractive cell source for cartilage regeneration, an inherent tendency to undergo hypertrophic maturation and endochondral ossification; as well as insufficient extracellular matrix production still prevent their clinical application in cell –based cartilage repair therapies. We recently demonstrated that intermittent treatment of MSC with parathyroid hormone-related protein (PTHrP) during in vitro chondrogenesis significantly enhanced extracellular matrix deposition and concomitantly reduced hypertrophy (1) opposite to constant PTHrP treatment, which strongly suppressed chondrogenesis via the cAMP/PKA pathway (2). Since signal timing seemed to be decisive for an anabolic versus catabolic outcome of the PTHrP treatment, we here aimed to investigate the role of PTHrP pulse frequency, pulse duration and total weekly exposure time in order to unlock the full potential of PTHrP pulse application to enhance and control MSC chondrogenesis.

Human bone marrow-derived MSC were subjected to in vitro chondrogenesis for six weeks. From day 7–42, cells were additionally exposed to 2.5 nM PTHrP(1–34) pulses or left untreated (control). Pulse frequency was increased from three times per week (3×6h/week) to daily, thereby maintaining either pulse duration (6h/d, total 42 h/week) or total weekly exposure time (2.6h/d, total 18 h/week).

A high frequency of PTHrP-treatment (daily) was important to significantly increase extracellular matrix deposition and strongly suppress ALP activity by 87 %; independent of the pulse duration. A long pulse duration was, however, critical for the suppression of the hypertrophic marker gene IHH, while MEF2C and IBSP were significantly suppressed by all tested pulse duration and frequency protocols. COL10A1, RUNX2 and MMP13 mRNA levels remained unaffected by intermittent PTHrP. A drop of Sox9 levels and a decreased proliferation rate after 6 hours of PTHrP exposure on day 14 indicated delayed chondroblast formation. Decreased IGFBP-2, -3 and -6 expression as well as decreased IGFBP-2 protein levels in culture supernatants suggested IGF-I-related mechanisms behind anabolic matrix stimulation by intermittent PTHrP.

The significant improvement of MSC chondrogenesis by the optimization of intermittent PTHrP application timing revealed the vast potential of PTHrP to suppress hypertrophy and stimulate chondrogenic matrix deposition. A treatment with PTHrP for 6 hours daily emerged as the most effective treatment mode. IGF-I and Sox-9 related mechanisms are suggested behind anabolic effects and delayed chondroblasts formation, respectively. Thus, similar to the established osteoporosis treatment, daily injections of PTHrP may become clinically relevant to support cartilage repair strategies relying on MSCs like subchondral bone microfracturing and autologous MSC implantation.

Summary Statment

The dual-mobility cup seems to bring more stability without changing the gait pattern.

Purpose

Plating remains the most widely employed method for the fixation of displaced diaphyseal clavicle fractures. The purpose of this study was to assess the efficacy and outcomes of diaphyseal clavicle fractures treated with intramedullary fixation using the Rockwood clavicle pin.

This study sought to determine if treatment of resistant clubfeet by the Ilizarov method influenced the pattern of recurrence. Forty-seven children were identified as having undergone treatment by the Ilizarov method. Inclusion criteria for treatment with the Ilizarov method were clubfeet belonging to diagnostic categories that had recognised tendencies for resistance to standard methods of clubfoot management or a previous history of soft tissue releases performed adequately but accompanied by rapid relapse.

There were 60 feet with a mean follow-up of 133 months (46-224). Diagnoses included 34 idiopathic types, 7 arthrogryposis, 1 cerebral palsy, and 5 other. Summary statistics and survival analysis was used; failure was deemed as a recurrence of fixed deformity necessitating further correction. This definition parallels clinical practice where attainment of ‘normal’ feet in this group remains elusive, and mild to moderate relapses that remain passively correctable are kept under observation.

Soft tissue releases were common primary or secondary procedures. The mean time to revision surgery, if a soft tissue release was undertaken as a primary procedure, was 36 months (SD 22), and 39 (SD 23) months if undertaken for the second time. This compares with 52 months (SD 32) if Ilizarov surgery was used. Using survival analysis, there is a 50% chance of a relapse sufficiently marked to need corrective surgery after 44 months following the first soft tissue release, 47 months if after the second soft tissue procedure and 120 months after the Ilizarov technique.

We conclude that resistant club feet, defined as those belonging to diagnostic categories with known poor prognoses or those that succumb to an early relapse despite adequate soft tissue surgery, may have longer relapse-free intervals if treated by the Ilizarov method.

Introduction: Trapeziectomy is a well established surgical procedure for the treatment of osteoarthritis of the carpo-metacarpal joint (CMCJ) o the thumb. The complications have been recognised in the past, but there has been limited literature describing the management and prognosis of long term complications following Trapeziectomy.

Aim: The purpose of our study was to describe our experience in management and prognosis of patients with long term complications associated with Trapeziectomy with particular references to residual pain and sensory branch of radial nerve (SBRN) paraesthesia.

Methods: 118 trapeziectomy procedures were performed in 103 patients for primary osteoarthritis of the CMCJ of thumb during the period of January 2000 – December 2005 at a single centre performed or supervised by a single surgeon (senior author). The data was obtained from the case notes retrospectively. The average follow up period was 12 months. The short term and long term complications and their management were recorded and analysed in detail.

Results: Long term complication rate was 23.7% (28 cases) which included 15 patients (12.7 %) complaining of residual pain at the base of the thumb, 6 patients (5.1%) had symptoms related to superficial branch of radial nerve and 2 patients (1.7%) had FCR rupture. Steroid injection was more successful than physiotherapy or splinting in majority of the patients with residual pain. Superficial branch of radial nerve symptoms resolved with time. However persistent symptoms were treated suceesfully by desensitization therapy.

Conclusion: Trapeziectomy is a fairly benign operation, but the complications are more than expected and the patients must be warned to expect long term complications. Most of the postoperative problems can be effectively managed non-operatively and the prognosis remains good in majority of the cases. Patients must be reassured to expect full recovery with time.

Background: We evaluate the role of percutaneous þxation of Acetabular fractures in a selected group of patients in which conservative management seemed unlikely to yield a satisfying outcome. Method: Between July 1998 and July 2001, 17 consecutive patients having suffered an Acetabular fracture underwent ßuoroscopic guided percutaneous þxation to stabilize the fracture. The mean age of the patients was 81 years (range 67 to 90). In all cases the fracture was non-displaced or minimally displaced (< 2 mm). The operative indication was based on our experience that these patients would have a less favorable outcome with conservative management due to their diminished general health and important associated morbidity. Percutaneous þxation was performed at a mean of four days post injury (range 2–6). In all cases, 2 cannulated cancellous 7.3 mm were used, one to þx the anterior column and the other, inserted in a retrograde fashion to stabilize the posterior column. Bed to armchair transfer began after 24 hours. Weight bearing as tolerated was allowed at 4 weeks from surgery. Two patients died of unrelated causes in the postoperative period and one patient was lost to follow-up, leaving fourteen patients who could be followed for a mean of 1,5 years (range 6 months-3 years). Results: Soft tissue dissection was minimal. There were no intra-operative or post-operative complications. At latest follow-up there was no evidence radiographically of displacement of fragments, degenerative changes or screw failure. Fracture union was achieved at a mean period of 12 weeks (range, 8–15 weeks) after surgery. In one case the tip of the posterior screw penetrated the sacroiliac joint, but no clinical adverse effects were noted. Clinical results was satisfactory in thirteen patients, and fair in one patient, as assessed by the Matta modiþcation of the rating system described by dñAubigne and Postel. Conclusion: Our results show that the percutaneous þxation is a valid therapeutic option in selected Acetabular fractures, and in the future broader indications may be found for this technique.

Aims: This study reports a retrospective review of notes and x-rays of 45 patients who underwent fixation of inter- and subtrochanteric fractures of the femur with the Intramedullary Hip Screw. Methods: 45 consecutive patients who underwent IMHS fixation between 1998 and 2001. Diagnoses: 24 intertrochanteric- and 15 subtrochanteric fractures, 2 prophylactic nailings for metastases, 4 reoperations for previously failed DHS/DCS. Data collected from patient notes included the intra-operative use of skeletal- vs. ski-boot traction, intra- and postoperative complications. X-ray review included classification of the fractures, grading of osteoporosis, measurement of neck-shaft angle, screw position in the femoral head, and distance from the screw to the nearest cortex. Results: The rate of intraoperative complications was 8,8%, post-operative complications occurred in 13,3% of the patients. The mortality rate within the first 3 months was 15,5%. Re-operations were necessary in 4,4% of the patients. The sliding screw was positioned in the middle sector of the femoral head in the coronal plane in 17 patients and in the sagittal plane in 14. Superior position occurred in 18 cases, inferior in 4, anterior in 4 and posterior in 16 patients. Conclusions: The main complication in our series was screw cut-out from the femoral head. This occurred in 4 patients, 2 of whom were previously failed DHS/DCS fixations. There was no single factor predicting implant failure. The results for primary fixations are comparable to most reported series in the literature and show that the outome is dictated by the original fracture pattern. There is a high failure rate if the implant is used for revision procedures.