Sustained release of locally delivered celecoxib provides pain relief for osteoarthritis: a proof of concept in dog patients.

OBJECTIVE: Drug delivery platforms that allow for gradual drug release after intra-articular administration have become of much interest as a treatment strategy for osteoarthritis (OA). The aim of this study was to investigate the safety and efficacy of an intra-articular sustained release formulation containing celecoxib (CXB), a cyclooxygenase-2 (COX-2) selective inhibitor. METHODS: Amino acid-based polyesteramide microspheres (PEAMs), a biodegradable and non-toxic platform, were loaded with CXB and employed in two in vivo models of arthritis: an acute inflammatory arthritis model in rats (n = 12), and a randomized controlled study in chronic OA dog patients (n = 30). In parallel, the bioactivity of sustained release of CXB was evaluated in monolayer cultures of primary dog chondrocytes under inflammatory conditions. RESULTS: Sustained release of CXB did not alleviate acute arthritis signs in the rat arthritis model, based on pain measurements and synovitis severity. However, in OA dog patients, sustained release of CXB improved limb function as objective parameter of pain and quality of life based on gait analysis and owner questionnaires. It also decreased pain medication dependency over a 2-month period and caused no adverse effects. Prostaglandin E2 levels, a marker for inflammation, were lower in the synovial fluid of CXB-treated dog OA patients and in CXB-treated cultured dog chondrocytes. CONCLUSION: These results show that local sustained release of CXB is less suitable to treat acute inflammation in arthritic joints, while safe and effective in treating pain in chronic OA in dogs.

A new 3D software for analysis and planning of lower limb and patellofemoral alignment: Reliability and accuracy.

BACKGROUND: The new software, mediCAD® 3D Knee Sport (mediCAD Hectec GmbH, Altdorf/Landshut, Germany), promises to combine automated digital 3D bone model generation, 3D analysis of lower limb geometry including analysis of the patellofemoral joint, and osteotomy planning. The aim of this study was to evaluate its reliability and accuracy. METHODS: In this retrospective multi-observer study, three post-mortem CTs were analysed by three observers at three points in time. Reliability was evaluated by calculating the intraclass correlation coefficient (ICC) of interobserver agreement. Accuracy was evaluated using the mean deviation D from the mean and the standard deviation SD from D. RESULTS: Ten of 18 alignment parameters showed excellent, two good and three moderate interobserver agreement. Poor agreement was found for the mechanical medial proximal tibial angle, the trochlear sulcus angle and trochlea depth. Mean interobserver ICC of all parameters ranged from 0.32 to 0.99. Fifteen of 18 parameters showed a low mean deviation D from the mean of < 2 mm / 2°. Three parameters related to the patellofemoral joint showed medium or high D (patella tilt, trochlear sulcus angle, patellar ridge angle). These parameters also showed the highest values for the SD of D. The trochlear sulcus angle was found to be the only parameter with high mean deviation (D ≥ 5 mm/5°) with D being 5.67 ± 3.23°. CONCLUSIONS: The current version of the software achieves good interobserver reliability and accuracy with the exception of a few measurement parameters.

Three-dimensional assessment of patellofemoral anatomy: Reliability and reference ranges.

BACKGROUND: Three-dimensional (3D) imaging and analysis offer new possibilities in preoperative diagnostics and surgical planning. Simultaneous 3D analysis of the joint angles and the patellofemoral anatomy allow for a realistic assessment of bony pathologies in patients with patellofemoral complaints. This study aims to develop a standardized and validated assessment of the 3D patellofemoral morphology and to establish reference ranges. METHODS: Thirteen patellofemoral anatomic landmarks were defined on 3D bone models of the lower limbs based on computer tomography data and evaluated regarding inter- and intra-observer variability. Further, 60 3D models of the lower limbs of young subjects without any previous knee operation/injury were assessed and rescaled reference values for relevant patellofemoral indices were obtained. RESULTS: The mean inter- and intra-observer deviation of all landmarks was below 2.3 mm. The interobserver intraclass correlation coefficient (ICC) was between 0.8 and 1.0 and the intra-observer ICC between 0.68 and 0.99 for all patellofemoral parameters. The calculated reference ranges are: Insall-Salvati index 1.0-1.4; patella tilt 6-18°; patella shift -4 to 3 mm; patella facet angle 118-131°; sulcus angle 141-156°; trochlear depth 3-6 mm; tibial-tuberosity to trochlear groove distance(TT-TG) 2D 14-21 mm; TT-TG 3D 11-18 mm; lateral trochlear inclination 13-23°; trochlear facet angle 43-65°. CONCLUSION: The demonstrated 3D analysis of the patellofemoral anatomy can be performed with high inter- and intra-observer correlation. Applying the obtained reference ranges and using existing 3D assessment tools for lower limb alignment, a preoperative 3D analysis and planning for complex knee procedures now is possible.

Three-dimensional assessment of lower limb alignment: Reference values and sex-related differences.

BACKGROUND: Three-dimensional (3D) preoperative planning and assisted surgery is increasingly popular in deformity surgery and arthroplasty. Reference ranges for 3D lower limb alignment are needed as a prerequisite for standardized analysis of alignment and preoperative planning in 3D, but are not yet established. METHODS: On 60 3D bone models of the lower limbs based on computed tomography data, fifteen parameters per leg were assessed by standardized validated 3D analysis. Distribution parameters and differences between sexes were evaluated. Reference values were generated by adding/subtracting one standard deviation from the mean. RESULTS: Women had a significantly lower mean mechanical lateral distal femoral angle compared with men (86.4 ±â€¯2.1° vs. 87.8 ±â€¯2.0°; P < .05) and significantly lower mean joint line convergence angle (-2.5 ±â€¯1.4° vs. -1.3 ±â€¯1.2; P < .01), but higher mean hip knee ankle angle (178.9 ±â€¯1.9° vs. 177.8 ±â€¯2.3°; P < .05) and mean femoral torsion (18.2 ±â€¯9.5° vs. 13.2 ±â€¯6.4°; P < .05), resulting in a tendency towards valgus alignment and vice versa for men. Differences in mean medial proximal tibial angle were not significant. The mean mechanical axis deviation from the tibial knee joint center was 6.9 ±â€¯7.3 mm medial and 1.4 ±â€¯16.1 mm ventral without significant differences between sexes. CONCLUSIONS: We describe total and sex-related reference ranges for all alignment relevant axes and joint angles of the lower limb. There are sex-related differences in certain alignment parameters, which should be considered in analysis and surgical planning.

Impacted Steel Sleeves for a minimally invasive approach in intramedullary nailing.

A custom-made instrument set of Steel Sleeves was developed to assist the insertion of reamers and intramedullary devices for fixation of long bone fractures or lengthening procedures with intramedullary nails. By use of the Steel Sleeves, migration of the entry point is prevented and protection of the bone and soft tissue at the entry point is guaranteed. In addition, the principle of a closed working channel for trans-articular approaches can be provided. In this article, a description of properties and clinical application of custom-made steel sleeve instrument set is provided.

Intraoperative customization of intramedullary nails - First results.

INTRODUCTION: Intramedullary nailing is a valuable treatment option for many types of fractures. Furthermore nailing is applicable for osteosynthesis following osteotomy in deformity correction. For intraoperative fine-tuning of alignment in intramedullary (IM) nailing procedures, a bending device for customization of IM nails under sterile conditions was developed. We have performed a retrospective clinical study to analyze and describe the technical requirements, indications and limitations for intraoperative customization of IM nails. MATERIALS AND METHODS: In 41 cases of deformity correction with IM nailing, we applied intraoperative sterile bending of IM nails. The patient age ranged from 13 to 64 years. We evaluated the radiological outcome (precision of the intervention) of 31 completed cases, comparing the preoperative planning with the final result on long-standing radiographs (LSR). The diameter of the nails ranged from 8,5mm to 13mm. Cases with fracture or non-union treatment with intraoperative application of the bending device were excluded and analyzed separately. RESULTS: All removed implants were examined - none of them showed any signs of material fatigue. The amount of intraoperative bending of the nails was 1° to 12°. A high level of precision was achieved, with a median postoperative axis deviation to the preoperative planning of 3,5mm. In a polio patient with limited bone quality, the implant removal caused an undisplaced cortical crack. There were no other complications. There was uneventful and fast bone healing in all patients. CONCLUSIONS: Intraoperative customization of intramedullary nails is a valuable technique for precise alignment control with IM nailing. With this technique, the benefits of IM nailing can be used for a wide range of indications, including deformity correction. The sterile bending device is safe and easy to handle. It is strong enough to bend all commercially available IM nails. Monofocal or linear bending in multiple planes is possible. However, when defining the site of bending, one must consider the removal of the implant in the future.

Three-dimensional assessment of lower limb alignment: Accuracy and reliability.

INTRODUCTION: Three-dimensional (3D) surgical planning and patient-specific implants are becoming increasingly popular in orthopedics and trauma surgery. In contrast to the established and standardized alignment assessment on two-dimensional (2D) long standing radiographs (LSRs) there is neither a standardized nor a validated protocol for the analysis of 3D bone models of the lower limb. This study aimed to create a prerequisite for pre-operative planning. METHODS: According to 2D analysis and after meticulous research, 24 landmarks were defined on 3D bone models obtained from computed axial tomography (CT) scans for a 3D alignment assessment. Three observers with different experience levels performed the test three different times on three specimens. Intraobserver and interobserver variability of the landmarks and the intraclass correlation coefficient (ICC) of the resulting axes and joint angles were evaluated. RESULTS: Overall, the intraobserver and interobserver variability was low, with a mean deviation <5 mm for all landmarks. The ICC of all joint angles and axis deviations was >0.8, except for tibial torsion (ICC = 0.69). All knee joint angles showed excellent ICC (>0.95). CONCLUSIONS: Using the defined landmarks, a standardized 3D alignment assessment with low intraobserver and interobserver variability and high ICC values for the knee joint angles can be performed regardless of examiner's experience. The described method serves as a reliable standardized protocol for a 3D malalignment test of the lower limb. Three-dimensional pre-operative analysis might enhance understanding of deformities and lead to a new focus in surgical planning.

Retinal specificity in eye fragments: investigations on the retinotectal projections of different quarter-eyes in Xenopus laevis.

According to Sperry's chemoaffinity hypothesis, the projection of a small eye fragment with a reduced amount of optic fibres should be restricted to that position in the optic tectum corresponding to its own specificity. However, previous investigations on different types of quarter-eyes in Xenopus laevis have revealed that their retinal projection was always restricted to the rostral part of the tectum, no matter what the origin of the remaining retinal quadrant. To get an indication of the state of specificity in such eye fragments, we investigated by electrophysiological and histological methods several features of the retinal projections of tempo-roventral (TV), naso-ventral (NV) and ventral (V) quarter-eyes which referred to their positional identity. Irrespective of their different origins, the projections were always located in the rostral part of the tectum, the size of the innervated tectal area depending for all fragment types on the size of the quarter-eyes, i.e. number of optic fibres. However, quantitative analyses revealed that with increasing eye size the various fragments expand their projections preferentially into those tectal areas that match their original specificity: TV projection is more concentrated in the rostral tectum, NV eyes expand their projections mainly to the caudal tectum, and V eyes enlarge their projections equally into the medial and caudal tectum. In addition, fibre-tracing experiments with cobaltic lysine showed that, according to the different origins of the quarter-eyes, retinal fibres follow the appropriate branch of the optic tract selectively: fibres of NV and V eyes pass mainly through the medial tract, and most fibres of TV eyes innervate the rostral tectum directly from a central position between the two side branches. All these findings suggest that the different types of quarter-eyes retain their original positional identity. Thus, their rostrally located retinotectal projections are not in register with their retinal specificity. We conclude that in X. laevis local positional markers in the tectum, if present at all, do not influence the development of the retinotectal projection. Instead we suggest a concept of self-sorting of the optic fibres, which can account for the partial innervation of the rostral tectum in different types of quarter-eyes.

Specificity and retinotectal projections of quarter-eye fragments in Xenopus laevis.

Three quarters of the eye anlage in Xenopus embryos of stage 33/34 were eliminated in three different sets of experiments. The remaining quadrant originated from the nasoventral part of the retina, from its ventral portion, or from the temporo-ventral area of the retina. All the fragments developed into small eyes of normal shape. The retinotectal connections did not deviate from those found in the control groups, even though mirror-image duplication was fairly frequent. For all fragments the tectal projection fields were rather limited. There was some indication of fragments retaining their original specificity. Irrespective, however, of their different origins, the optic projections always occupied the rostrolateral area of the tectum.

The retinotectal projection of quarter eyes in Xenopus laevis.

Following extirpation of three quarters of the eye anlage of Xenopus laevis in stage 33/34, the remaining quadrants developed into small eyes of normal shape. Irrespective of the different portions of the eye anlage the quarter eyes originated from, the retinotectal projection was always confined to the rostrolateral part of the tectum, forming an orderly map, and its dimensions corresponded to the size of the contralateral eye. Therefore, it was suggested that during development both size and location of the projection are independent of the existence of tectal markers. Instead, they are determined by the number of ingrowing optic fibers and the direction of their growth from the rostral origin.