Thomas Gösling

Caspase 8 small interfering RNA prevents acute liver failure in mice

A major concern in therapy of acute liver failure is protection of hepatocytes to prevent apoptosis and maintain liver function. Small interfering RNA (siRNA) is a powerful tool to silence gene expression in mammalian cells. To evaluate the therapeutic efficacy of siRNA in vivo we used different mouse models of acute liver failure. We directed 21-nt siRNAs against caspase 8, which is a key enzyme in death receptor-mediated apoptosis. Systemic application of caspase 8 siRNA results in inhibition of caspase 8 gene expression in the liver, thereby preventing Fas (CD95)-mediated apoptosis. Protection of hepatocytes by caspase 8 siRNA significantly attenuated acute liver damage induced by agonistic Fas (CD95) antibody (Jo2) or by adenovirus expressing Fas ligand (AdFasL). However, in a clinical situation the siRNAs most likely would be applied after the onset of acute liver failure. Therefore we injected caspase 8 siRNA at a time point during AdFasL- and adenovirus wild type (Adwt)-mediated liver failure with already elevated liver transaminases. Improvement of survival due to RNA interference was significant even when caspase 8 siRNA was applied during ongoing acute liver failure. In addition, it is of particular interest that caspase 8 siRNA treatment was successful not only in acute liver failure mediated by specific Fas agonistic agents (Jo2 and AdFasL) but also in acute liver failure mediated by Adwt, which is an animal model reflecting multiple molecular mechanisms involved in human acute viral hepatitis. Consequently, our data raise hope for future successful application of siRNA in patients with acute liver failure.

Single lateral locked screw plating of bicondylar tibial plateau fractures.

We prospectively followed a case series of 68 patients with 69 AO/ASIF 41-C-type fractures treated with the Less Invasive Stabilization System for the proximal lateral tibia. We assessed malreduction, secondary loss of reduction, and infection rates in patients with a locked screw plate for unilateral fixation of bicondylar fractures. Sixty-two (91%) patients returned for final followup (range, 11-13 months). Malreduction and malalignment were defined as an intraarticular step-off of 2 mm or greater, or as a malalignment in the frontal or sagittal plane greater than 5°. Fourteen fractures were open. Primary bone grafting was done in 13 patients. Significant malreduction was seen in 16 patients. There were four superficial infections and one deep infection. One fracture did not heal, and nine patients had substantial loss of reduction. Unilateral locked screw plating is a good alternative for treatment of problematic fractures of the tibial plateau that are associated with soft tissue damage and metaphyseal comminution. The reduction technique for exact alignment is demanding. Level of Evidence: Therapeutic Study, Level IV (case series). See Guidelines for Authors for a complete description of levels of evidence.

Less Invasive Stabilization of Complex Tibial Plateau Fractures : A Biomechanical Evaluation of a Unilateral Locked Screw Plate and Double Plating

Objective: To compare the vertical subsidence in a bicondylar tibial plateau fracture model stabilized either by a unilateral locked screw plate (LSP) or by double plating. Design: Biomechanical cadaver study. Intervention: A 41-C1 fracture model was created in eight pairs of fresh-frozen human cadaver tibiae. Stabilization was performed either by open reduction and internal fixation (ORIF) using a lateral L-buttress plate and a medial four-hole, one-third tubular antiglide-plate or by a lateral LSP. Four load levels (400N, 800N, 1200N, 1600N), each with five cycles, were consecutively applied to the medial plateau. Main Outcome Measurements: The vertical plastic deformation at the end of each cycle was the main parameter of interest. Statistical analysis was performed with the two-way ANOVA test for repeated measurements. Each individual loading level was analyzed separately using Student t test. Results: In one pair, both fixation techniques failed at the first loading cycle of 1200N. One ORIF fixation failed at the first loading cycle of 1600N. The average plastic vertical subsidence was 0.40 mm (LSP) and 0.25 mm (ORIF) at 400N (P = 0.291), 0.83 mm (LSP) and 0.81 mm (ORIF) at 800N (P = 8.82), 1.06 mm (LSP) and 0.96 mm (ORIF) at 1200N (P = 0.98), and 1.54 mm (LSP) and 1.14 mm (ORIF) at 1600N (P = 0.53). Vertical subsidence depended on the applied load (P = 0.002), but not on the method of fixation (P = 0.236). Conclusion: Both fixation techniques have a high resistance to vertical subsidence even with loads exceeding the average body weight. No statistically significant difference was seen between the two methods of fixation.

A comparison of plates with and without locking screws in a calcaneal fracture model.

Background: We compared different plates in an experimental calcaneal fracture model under biocompatible loading. Methods: Four plates were tested: a plate without locked screws (Synthes), and three different plates with locked screws (Newdeal, Darco, Synthes). Synthetic calcanei (Sawbone) were osteotomized to create a fracture model, and the plates were fixed onto them. Seven specimens for each plate model were subjected to cyclic loading (preload 20 N, 1,000 cycles with 800 N, 0.75 mm/s), and load to failure (0.75 mm/s). Motion, forces, plastic deformation of the plate, and consequent depression of the posterior joint facet were analyzed. Results: During cyclic loading, all plates with locked screws showed statistically significant lower displacement in the primary loading direction than the plates without locked screws. Mean values (mm) of maximal displacements for each plate during cyclic loading were as follows: Synthes, 3.5; Darco, 4.5; Newdeal, 5.0; Synthes without locked screws, 7.5; (p < 0.001). No statistically significant differences between the plates were found in relation to loads to failure and corresponding displacement. Conclusion: This is the first biomechanical study to assess the stability of different plates currently in use in our practice for the fixation of calcaneal fractures. Our results showed that plates with locked screws provided greater stability during cyclic loading than the plate without locked screws.

Computer-assisted analysis of lower limb geometry: higher intraobserver reliability compared to conventional method

Exact radiographic evaluation of lower limb alignment, joint orientation and leg length is crucial for preoperative planning and successful treatment of deformities, fractures and osteoarthritis. Improvement of the accuracy of radiographic measurements is highly desirable. To determine the intraobserver reliability of conventional analysis of lower extremity geometry, 59 long leg radiographs were randomly analyzed 5 times by a single surgeon. The measurements revealed a standard deviation between 0.36° and 1.17° for the angles mLPFA, mLDFA, MPTA, LDTA, JLCA and AMA (nomenclature according to Paley), and 0.94 mm and 0.90 mm for the MAD and leg length, respectively. Computer-assisted analysis with a special software significantly reduced the standard deviation of the mLDFA, MPTA, LDTA, JLCA (each p < 0.001), AMA (p = 0.032) and MAD (p = 0.023) by 0.05–0.36° and 0.14 mm, respectively. Measuring time was reduced by 44% to 6:34 ± 0:45 min (p < 0.001). Digital calibration by the software revealed an average magnification of conventional long leg radiographs of 4.6 ± 1.8% (range: 2.7–11.9%). Computer-assisted analysis increases the intraobserver reliability and reduces the time needed for the analysis. Another major benefit is the ease of storage and transfer of digitized images. Due to the varying magnification factors on long leg radiographs, the use of magnification markers for calibration is recommended.

Navigated intraoperative analysis of lower limb alignment

Introduction: Accurate intraoperative assessment of lower limb alignment is crucial for the treatment of long bone fractures, implantation of knee arthroplasties and correction of deformities. During orthopaedic surgery, exact real time control of the mechanical axis is strongly desirable. The aim of this study was to compare conventional intraoperative analysis of the mechanical axis by the cable method with continuous, 3-dimensional imaging with a navigation system. Materials and methods: Twenty legs of fresh human cadaver were randomly assigned to conventional analysis with the cable method (n=10) or navigated analysis with a fluoroscopy based navigation system (n=10). The intersection of the mechanical axis with the tibia plateau was presented as percentage of the tibia plateau (beginning with 0% at the medial border and ending with 100% laterally). CT-scans were performed for all legs and the CT-values of the mechanical axis were compared to the measurements after cable method and navigation. Furthermore, the radiation time and dose area product of both groups for single analysis of the mechanical axis was compared. Results: Conventional evaluation of the mechanical axis by the cable method showed 6.0±3.1% difference compared to the analysis by CT. In the navigated group the difference was 2.6±1.8% (P=0.008). Radiation time and dose area product were highly significantly lower after conventional measurement. Conclusions: Navigated intraoperative evaluation of the mechanical axis offers increased accuracy compared to conventional intraoperative analysis. Furthermore, navigation provides continuous control not only of the mechanical axis, but also of the sagittal and transverse plane. Using the cable method, radiation exposure depends on the number of measurements and is lower compared to the navigation system for single intraoperative analysis of the mechanical axis, but may be higher in case of repeated intraoperative measurements.

Robot-assisted Long Bone Fracture Reduction

The preferred treatment of femoral (thigh bone) shaft fractures nowadays is the minimally invasive technique of intramedullary nailing. However, in addition to its advantages, this technique also has a number of disadvantages, such as the frequent occurrence of malaligned fracture reductions and high X-ray exposure, especially to the operating team. The aim of our research is to overcome these shortcomings by utilizing modern techniques such as three-dimensional (3D) imaging, navigation, and robotics. In this paper we present the current state of our interdisciplinary research project. We first introduce a telemanipulated fracture reduction procedure, which is based on 3D imaging data. This set-up is improved one step further towards an automated fracture reduction procedure. Finally, two drilling tasks, namely the opening of the medullar cavity and the distal locking of the intramedullary nail, are presented, which are supported by automated X-ray-based image analysis and robot-assisted drill guidance. We show that high reduction accuracies can be achieved with our robotic system. Furthermore, the robot-assisted drill guidance achieves superior results with respect to increased precision and decreased X-ray exposure compared with the conventional procedure. We conclude that this surgical procedure benefits conspicuously from the support of robotic assistance systems and that further research and development in this field is worthwhile.

Robot-assisted fracture reduction: A preliminary study in the femur shaft

Reduction in femoral shaft fractures can be difficult to achieve with minimally invasive techniques. Malalignment and high intra-operative radiation exposure can result. The hypothesis was that robot-assisted fracture reduction could improve the quality of reduction while reducing the amount of radiation exposure. A robot system was developed that allows fracture manipulation with a joystick as input device. The system provides the surgeon with haptic and metric feedback. Fifteen synthetic femurs were broken and reduced by simulated open (group A) and closed techniques (group B). These techniques were compared with the robot-assisted reduction with (group C) and without (group D) haptic and metric information. An image intensifier was simulated with two orthogonal cameras. All reduction techniques showed minor malalignment. In group C, the alignment was: procurvatum/recurvatum 0.6° (0–2.0°); varus/valgus 0.8° (0–3.0°); and axial rotation 0.8° (0–3.1°). A significant difference was seen between the groups (two-way ANOVA, p<0.001). Axial rotation was significantly lower in group C than in group B (1.9°; p<0.001). The residual varus and valgus deviation was higher in group C compared with group A (0.4°, p=0.03). The median number of simulated radiographs was significantly less in group C (35) compared with group D (72; p<0.001) and group B (49; p=0.01). Robot-assisted fracture reduction of the femur provides high precision in alignment while reducing the amount of intraoperative imaging. Further research in this field is worthwhile.

Femoral nail removal should be restricted in asymptomatic Patients

Femoral nail removal has been suggested as a routine procedure for symptomatic and asymptomatic patients. The aim of this study was to evaluate whether asymptomatic patients have long-term complaints after femoral nail removal. Additionally, factors that might extend operation time and effect soft tissue healing negatively were analyzed. A retrospective study on the removal of 164 femoral nails after fracture consolidation was done. A review of the patient charts and radiographs was done. Neither the interval between nail implantation and nail removal or the use of an end-cap significantly influenced the operation time. The surgeon’s qualification and nail depth were the only variables that influenced operation time. Neither operation time, nail depth, surgeon’s qualification, nor the grade of heterotopic ossification significantly influenced the incidence of wound healing problems. One hundred nine patients (73%) were available for the followup interview. Preoperatively, 58 patients (53%) had local complaints. Of these 58 patients, 78% reported improvement and 7% reported an aggravation of their local complaints. Of the 51 patients who were asymptomatic before surgery, 20% reported long-term complaints at followup. Only symptomatic patients should be considered for femoral nail removal.

Limb lengthening with the Intramedullary Skeletal Kinetic Distractor (ISKD).

ZusammenfassungOperationszielKallusdistraktion von Femur oder Tibia durch ein intramedulläres Implantat, welches sich mechanisch durch alternierende Rotationsbewegungen von mindestens 3° verlängert.IndikationenBeinverkürzungen des Femurs oder der Tibia zwischen 20 und 80 mm.Gleichzeitige Korrektur von Achsendeformitäten im Bereich der Osteotomie möglich.KontraindikationenOffene Wachstumsfugen.Unzureichender Markrauminnendurchmesser (nach Aufbohrung des Femurs < 14,5 mm, der Tibia < 12,5 mm).Mangelnde Mitarbeit des Patienten.Ausgeprägte Fehlstellungen.Osteitis.Weichteilinfekte.OperationstechnikRückenlagerung. Am Femur im proximalen oder mittleren Schaftdrittel Osteotomie nach fächerförmigen queren Anbohrungen, unter Rotationskontrolle mit zwei 3,0-mm-Kirschner-Drähten. An der Tibia quere Osteotomie mit einer Gigli-Säge. Korrektur von Achsen- oder Rotationsfehlstellungen. Antegrades Aufbohren der Markhöhle am Femur 2,0 mm, an der Tibia 1,5 mm über den geplanten Nageldurchmesser. Einführen des Intramedullary Skeletal Kinetic Distractor (ISKD) in den Markraum, distale Verriegelung in Freihandtechnik, Kontrolle der Rotation sowie des Osteotomiespalts und proximale Verriegelung mit einem Zielgerät. Intraoperative Kontrolle der Distraktion des ISKD über einen externen Monitor. Am Femur 3 Tage und an der Tibia 5 Tage postoperativ Beginn zunehmender Mobilisation, um eine tägliche Distraktion von etwa 1 mm zu erreichen. Bei unzureichender Verlängerung führt der Patient gezielte Rotationsbewegungen durch, bis die erwünsche Verlängerung erreicht ist.ErgebnisseVier Patienten mit einem mittleren Alter von 29 Jahren (18–36 Jahre) wurde ein ISKD implantiert. Neben drei posttraumatischen Femurverkürzungen wurde eine kongenitale Tibiaverkürzung behandelt. Zwei Femora wiesen präoperativ komplexe Fehlstellungen auf. Die durchschnittliche Verlängerung betrug 31 mm (26–40 mm).Der intraoperative Blutverlust betrug 230 ml (100–320 ml), die durchschnittliche Operationszeit 108 min (90–145 min). Die tägliche Distraktionsstrecke belief sich im Durchschnitt auf 1,2 mm (0,9–1,8 mm). Vollbelastung wurde nach 10 Wochen (7–14 Wochen) gestattet, Arbeitsfähigkeit bestand nach 11 Wochen (7–16 Wochen).Bei der Nachuntersuchung durchschnittlich 2,3 Jahre postoperativ bestanden keine Einschränkungen der Kniegelenkbeweglichkeit. Das Kallusregenerat war 80 Tage (51–111 Tage) nach der Operation knöchern durchbaut bei einem mittleren Heilungsindex von 2,9 Tagen/mm (1,8–4,1 Tage/mm). Innerhalb des Beobachtungszeitraums waren keine Komplikationen aufgetreten. Gemäß dem Paley-Score erreichten alle Patienten ein exzellentes Ergebnis.AbstractObjectiveCallus distraction of the femur or tibia with an intramedullary distractor, which lengthens mechanically through alternating rotations of at least 3°.IndicationsFemoral or tibial shortening between 20 and 80 mm.Angular and rotational deformities can be corrected at the osteotomy site.ContraindicationsOpen epiphyses.Small medullary canal (after intramedullary reaming femoral diameter < 14.5 mm, tibial diameter < 12.5 mm).Severe deformities.Insufficient compliance.Osteitis.Soft-tissue infections.Surgical TechniqueSupine position. Femoral shaft osteotomy at the proximal or middle third by multiple drill holes completed with a chisel. For lengthening of the tibia, osteotomy with a Gigli saw is preferred. Control of the rotation by two parallel 3.0-mm Kirschner wires. Correction of angular or rotational deformities. Via stab incision reaming of the medullary canal with a flexible reamer. The femur is overreamed 2.0 mm and the tibia 1.5 mm above the desired implant diameter. Insertion of the Intramedullary Skeletal Kinetic Distractor (ISKD) into the medullary canal and distal locking in freehand technique. Control of the rotation and of the osteotomy gap. Proximal locking with an aiming device. For femoral lengthening 3 days and for tibial lengthening 5 days postoperatively the distraction is begun by increasing mobilization with partial weight bearing, to achieve daily distraction of 1 mm. In case of insufficient distraction, additional rotations are performed by the patient while checking the external monitor that displays the daily and total distraction length.ResultsIntramedullary lengthening with the ISKD was performed in four patients having an average age of 29 years (18–36 years). Two femoral shortenings were combined with complex rotational and angular deformities. The average lengthening of three femora and one tibia was 31 mm (26–40 mm).The average intraoperative blood loss was 230 ml (110–320 ml), the mean surgical time 108 min (90–145 min). The average daily distraction amounted to 1.2 mm (0.9–1.8 mm). Full weight bearing was permitted after 10 weeks (7–14 weeks), return to regular work after 11 weeks (7–16 weeks).At follow-up examination of an average of 2.3 years postoperatively the knee range of motion was full. Consolidation was noted 80 days (51–111 days) postoperatively with an average consolidation index of 2.9 days/mm (1.8–4.1 days/mm). No complications were observed. According to the Paley Score all patients had an excellent outcome.OBJECTIVE Callus distraction of the femur or tibia with an intramedullary distractor, which lengthens mechanically through alternating rotations of at least 3 degrees. INDICATIONS Femoral or tibial shortening between 20 and 80 mm. Angular and rotational deformities can be corrected at the osteotomy site. CONTRAINDICATIONS Open epiphyses. Small medullary canal (after intramedullary reaming femoral diameter < 14.5 mm, tibial diameter < 12.5 mm). Severe deformities. Insufficient compliance. Osteitis. Soft-tissue infections. SURGICAL TECHNIQUE Supine position. Femoral shaft osteotomy at the proximal or middle third by multiple drill holes completed with a chisel. For lengthening of the tibia, osteotomy with a Gigli saw is preferred. Control of the rotation by two parallel 3.0-mm Kirschner wires. Correction of angular or rotational deformities. Via stab incision reaming of the medullary canal with a flexible reamer. The femur is overreamed 2.0 mm and the tibia 1.5 mm above the desired implant diameter. Insertion of the Intramedullary Skeletal Kinetic Distractor (ISKD) into the medullary canal and distal locking in freehand technique. Control of the rotation and of the osteotomy gap. Proximal locking with an aiming device. For femoral lengthening 3 days and for tibial lengthening 5 days postoperatively the distraction is begun by increasing mobilization with partial weight bearing, to achieve daily distraction of 1 mm. In case of insufficient distraction, additional rotations are performed by the patient while checking the external monitor that displays the daily and total distraction length. RESULTS Intramedullary lengthening with the ISKD was performed in four patients having an average age of 29 years (18-36 years). Two femoral shortenings were combined with complex rotational and angular deformities. The average lengthening of three femora and one tibia was 31 mm (26-40 mm). The average intraoperative blood loss was 230 ml (110-320 ml), the mean surgical time 108 min (90-145 min). The average daily distraction amounted to 1.2 mm (0.9-1.8 mm). Full weight bearing was permitted after 10 weeks (7-14 weeks), return to regular work after 11 weeks (7-16 weeks). At follow-up examination of an average of 2.3 years postoperatively the knee range of motion was full. Consolidation was noted 80 days (51-111 days) postoperatively with an average consolidation index of 2.9 days/mm (1.8-4.1 days/mm). No complications were observed. According to the Paley Score all patients had an excellent outcome.