The biodistribution of triamcinolone acetonide injections in severe keloids: an exploratory three-dimensional fluorescent cryomicrotome study.

Intralesional corticosteroid injections are a first-line treatment for keloids; yet clinical treatment results are highly variable and often suboptimal. Variation in triamcinolone acetonide (TAC) biodistribution may be an important reason for the variable effects of TAC treatment in keloids. In this exploratory study we investigated the biodistribution of TAC in keloids and normal skin using different drug delivery techniques. Fluorescent-labeled TAC suspension was administered into keloids and normal skin with a hypodermic needle and an electronic pneumatic jet injector. TAC biodistribution was represented by the fluorescent TAC volume and 3D biodistribution shape of TAC, using a 3D-Fluorescence-Imaging Cryomicrotome System. Twenty-one keloid and nine normal skin samples were analyzed. With needle injections, the mean fluorescent TAC volumes were 990 µl ± 479 in keloids and 872 µl ± 227 in normal skin. With the jet injector, the mean fluorescent TAC volumes were 401 µl ± 252 in keloids and 249 µl ± 67 in normal skin. 3D biodistribution shapes of TAC were highly variable in keloids and normal skin. In conclusion, TAC biodistribution in keloids is highly variable for both needle and jet injection. This may partly explain the variable treatment effects of intralesional TAC in keloids. Future research is needed to confirm this preliminary finding and to optimize drug delivery in keloids.

A three-dimensional algorithm for precise measurement of human auricle parameters.

Measurement of auricle parameters for planning and post-operative evaluation presents substantial challenges due to the complex 3D structure of the human auricle. Traditional measurement methods rely on manual techniques, resulting in limited precision. This study introduces a novel automated surface-based three-dimensional measurement method for quantifying human auricle parameters. The method was applied to virtual auricles reconstructed from Computed Tomography (CT) scans of a cadaver head and subsequent measurement of important clinically relevant aesthetical auricular parameters (length, width, protrusion, position, auriculocephalic angle, and inclination angle). Reference measurements were done manually (using a caliper and using a 3D landmarking method) and measurement precision was compared to the automated method. The CT scans were performed using both a contemporary high-end and a low-end CT scanner. Scans were conducted at a standard scanning dose, and at half the dose. The automatic method demonstrated significantly higher precision in measuring auricle parameters compared to manual methods. Compared to traditional manual measurements, precision improved for auricle length (9×), width (5×), protrusion (5×), Auriculocephalic Angle (5-54×) and posteroanterior position (23×). Concerning parameters without comparison with a manual method, the precision level of supero-inferior position was 0.489 mm; and the precisions of the inclination angle measurements were 1.365 mm and 0.237 mm for the two automated methods investigated. Improved precision of measuring auricle parameters was associated with using the high-end scanner. A higher dose was only associated with a higher precision for the left auricle length. The findings of this study emphasize the advantage of automated surface-based auricle measurements, showcasing improved precision compared to traditional methods. This novel algorithm has the potential to enhance auricle reconstruction and other applications in plastic surgery, offering a promising avenue for future research and clinical application.

Non-invasive quantitative assessment of induced component displacement can safely and accurately diagnose tibial component loosening in patients: A prospective diagnostic study.

PURPOSE: Aseptic loosening often requires major, expensive and invasive revision surgery. Current diagnostic modalities merely show indirect signs of loosening. A recent proof of concept study proposed a non-invasive technique for the quantitative and visual assessment of implant movement as a diagnostic aid for tibial component loosening. The primary research question addressed is whether this novel diagnostic modality can safely and effectively aid the diagnosis of aseptic loosening. METHODS: This clinical study included patients suspected of aseptic total knee arthroplasty (TKA) loosening listed for revision surgery and asymptomatic patients. Safety was evaluated using a numerical rating scale (NRS) for discomfort and by registration of adverse events. Feasibility was assessed by recording the duration and ease of the procedure. Intra- and interrater reliability were evaluated. In symptomatic patients, diagnostic accuracy metrics were evaluated with intra-operative assessment as a reference test. RESULTS: In total, 34 symptomatic and 38 asymptomatic knees with a TKA were analysed. The median NRS for discomfort during loading was 6 (interquartile range [IQR]: 3.75-7.00) in symptomatic patients and 2 (IQR: 1.00-3.00) in asymptomatic patients. No adverse events were reported. The majority of users found the use of the loading device easy. The median time spent in the computed tomography room was 9 min (IQR: 8.00-11.00). Excellent to good intra- and interrater reliabilities were achieved. Diagnostic accuracy analysis resulted in a sensitivity of 0.91 (95% confidence interval [CI]: 0.72-0.97) and a specificity of 0.72 (95% CI: 0.43-0.90). CONCLUSIONS: The proposed diagnostic method is safe, feasible, reliable and accurate in aiding the diagnosis of aseptic tibial component loosening. LEVEL OF EVIDENCE: Level II.

Minimal but potentially clinically relevant anteroinferior position of the humeral head following traumatic anterior shoulder dislocations: A 3D-CT analysis.

In unstable shoulders, excessive anteroinferior position of the humeral head relative to the glenoid can lead to a dislocation. Measuring humeral head position could therefore be valuable in quantifying shoulder laxity. The aim of this study was to measure (1) position of the humeral head relative to the glenoid and (2) joint space thickness during passive motion in unstable shoulders caused by traumatic anterior dislocations and in contralateral uninjured shoulders. A prospective cross-sectional CT-study was performed in patients with unilateral anterior shoulder instability. Patients underwent CT scanning of both injured and uninjured side in supine position (0° abduction and 0° external rotation) and in 60°, 90°, and 120° of abduction with 90° of external rotation without an external load. Subsequently, 3D virtual models were created of the humerus and the scapula to create a glenoid coordinate system to identify poster-anterior, inferior-superior, and lateral-medial position of the humeral head relative to the glenoid. Joint space thickness was defined as the average distance between the subchondral bone surfaces of the humeral head and glenoid. Fifteen consecutive patients were included. In supine position, the humeral head was positioned more anteriorly (p = 0.004), inferiorly (p = 0.019), and laterally (p = 0.021) in the injured compared to the uninjured shoulder. No differences were observed in any of the other positions. A joint-space thickness map, showing the bone-to-bone distances, identified the Hill-Sachs lesion footprint on the glenoid surface in external rotation and abduction, but no differences on average joint space thickness were observed in any position.

Performance of the Aptis Distal Radioulnar Joint Implant: A Clinical Case Series Including Four-Dimensional Computed Tomography Kinematic Analysis.

High complication rates and surgical revision rates following Aptis implant placement have been reported in the literature. This study evaluates the performance of the Aptis implant of twelve patients using four-dimensional kinematic analysis. The (mean) follow-up was 58 months. Wrist motion, grip strength, and kinematic analysis of both arms were used to investigate possible causes of the reported complications. In nine cases (75%), the proximal to distal translation of the distal radius along the ulnar axis in the affected forearm was too little or absent. Significant correlations were found between postoperative extension and translation of the distal radius along the ulnar axis and between the radial deviation and combined error. The four-dimensional kinematic analysis suggests that the current design of the implant could lead to limited restoration of the position of the forearm rotation axis and the translation of the radius along the ulnar axis.

Promising results of an non-invasive measurement of knee implant loosening using a loading device, CT-scans and 3D image analysis.

BACKGROUND: After total knee arthroplasty up to 13% requires revision surgery to address loosening. No current diagnostic modalities have a sensitivity or specificity higher than 70-80% to detect loosening, leading to 20-30% of patients undergoing unnecessary, risky and expensive revision surgery. A reliable imaging modality is required to diagnose loosening. This study presents a new and non-invasive method and evaluates its reproducibility and reliability in a cadaveric study. METHODS: Ten cadaveric specimens were implanted with a loosely fitted tibial components and CT scanned under load towards valgus and varus using a loading device. Advanced three-dimensional imaging software was used to quantify displacement. Subsequently, the implants were fixed to the bone and scanned to determine the differences between the fixed and the loose state. Reproducibility errors were quantified using a frozen specimen in which displacement was absent. FINDINGS: Reproducibility errors, expressed as mean target registration error, screw-axis rotation and maximum total point motion were 0.073 mm (SD 0.033), 0.129 degrees (SD 0.039) and 0.116 mm (SD 0.031), respectively. In the loose condition, all displacements and rotation changes were larger than the reported reproducibility errors. Comparing the mean target registration error, screw axis rotation and maximum total point motion in the loose condition to the fixed condition resulted in mean differences of 0.463 mm (SD 0.279; p = 0.001), 1.769 degrees (SD 0.868; p < 0.001) and 1.339 mm (SD 0.712; p < 0.001), respectively. INTERPRETATION: The results of this cadaveric study show that this non-invasive method is reproducible and reliable for detection of displacement differences between fixed and loose tibial components.

Madelung Deformity: Radioscapholunate Arthrodesis With a Neo-DRUJ.

BACKGROUND: Madelung deformity is a rare wrist anomaly that causes considerable pain while restricting function. In this study, we describe a radioscapholunate (RSL) arthrodesis with a neo-distal radioulnar joint (DRUJ) in Madelung deformity patients with an abnormal sigmoid notch and compare results to patients after a reverse wedge osteotomy. METHODS: Six wrists underwent RSL arthrodesis with a neo-DRUJ in a two-phase approach: (1) modified RSL arthrodesis with triquetrectomy; and (2) distal scaphoidectomy. Seven wrists underwent a reverse wedge osteotomy procedure. RESULTS: There were no differences found in postoperative pain, grip strength, or range of motion (ROM), apart from extension, which was decreased after RSL arthrodesis with a neo-DRUJ. Quality of life and Michigan Hand Outcomes Questionnaire scores were similar. CONCLUSIONS: Although clinical outcome parameters are not different among the two groups, the RSL arthrodesis with construction of a neo-DRUJ could prove a valid treatment option for a subset of patients with a severely affected sigmoid notch.

Kinematic analysis of forearm rotation using four-dimensional computed tomography.

This study aimed to quantify forearm kinematics with a focus on the forearm rotation axis. Ten healthy volunteers were included in the study. One three-dimensional computed tomographic scan and two four-dimensional computed tomographic scans were done in all the arms to capture forearm joint motion. After image processing, the rotation axis and the movement of the radius with respect to various axes were quantified. The rotation axis was calculated using finite helical axis analysis and a circle fitting approach. The mean error of the rotation axis found through circle fitting was 0.2 mm (SD 0.1) distally and 0.1 mm (SD 0.1) proximally, indicating an improvement in precision over the finite helical axis approach. The translations of the radius along the ulnar axis and the forearm rotation axis were 2.6 (SD 0.8) and 0.6 mm (SD 0.9), respectively. The rotation of the radius around the radial axis was 7.2°. The techniques presented provide a detailed description of forearm kinematics.

Translation of 3D Anatomy to 2D Radiographic Angle Measurements in the Ankle Joint: Validity and Reliability.

Background: The objective consisted of 2 elements, primarily to define 2 bone geometry variations of the ankle that may be of prognostic value on ankle instability and secondly to translate these bone variations from a 3D model to a simple 2D radiographic measurement for clinical use. Methods: The 3D tibial and talar shape differences derived from earlier studies were translated to two 2D radiographic parameters: the medial malleolar height angle (MMHA) and talar convexity angle (TCA) respectively to ensure clinical use. To assess validity, the MMHA and TCA were measured on 3D polygons derived from lower leg computed tomographic (CT) scans and 2D digitally reconstructed radiographs (DRRs) of these polygons. To assess reliability, the MMHA and TCA were measured on standard radiographs by 2 observers calculating the intraclass correlation coefficient (ICC). Results: The 3D angle measurements on the polygons showed substantial to excellent agreement with the 2D measurements on DRR for both the MMHA (ICC 0.84-0.93) and TCA (ICC 0.88-0.96). The interobserver reliability was moderate with an ICC of 0.58 and an ICC of 0.64 for both the MMHA and TCA, respectively. The intraobserver reliability was excellent with an ICC of 0.96 and 0.97 for the MMHA and the TCA, respectively. Conclusion: Two newly defined radiographic parameters (MMHA and TCA) are valid and can be assessed with excellent intraobserver reliability on standard radiographs. The interobserver reliability was moderate and indicates training is required to ensure uniformity in measurement technique. The current method may be used to translate more variations in bone shape prior to implementation in clinical practice. Level of Evidence: Level III, cohort study.

Difference in orientation of the talar articular facets between healthy ankle joints and ankle joints with chronic instability.

Since both the talocrural and subtalar joints can be involved in chronic ankle instability, the present study assessed the talar morphology as this bone is the key player between both joint levels. The 3D orientation and curvature of the superior and the posteroinferior facet between subjects with chronic ankle instability and healthy controls were compared. Hereto, the talus was segmented in the computed tomography images of a control group and a chronic ankle instability group, after which they were reconstructed to 3D surface models. A cylinder was fitted to the subchondral articulating surfaces. The axis of a cylinder represented the facet orientation, which was expressed by an inclination and deviation angle in a coordinate system based on the cylinder of the superior talar facet and the geometric principal axes of the subject's talus. The curvature of the surface was expressed as the radius of the cylinder. The results demonstrated no significant differences in the radius or deviation angle. However, the inclination angle of the posteroinferior talar facet was significantly more plantarly orientated (by 3.5°) in the chronic instability group (14.7 ± 3.1°) compared to the control group (11.2 ± 4.9°) (p < 0.05). In the coronal plane this corresponds to a valgus orientation of the posteroinferior talar facet relative to the talar dome. In conclusion, a more plantarly and valgus orientated posteroinferior talar facet may be associated to chronic ankle instability.

Comparison of an oblique single cut rotation osteotomy with a novel 3D computer-assisted oblique double cut alignment approach.

An oblique double-cut rotation osteotomy (ODCRO) enables correcting a complex bone deformation by aligning, in 3D, the distal, middle and proximal bone segments with a target bone, without intersegmental gaps. We propose virtual preoperative planning of an ODCRO. To minimize a residual translation error, we use an optimization algorithm and optimize towards bone length, alignment in the transverse direction, or a balanced reconstruction. We compare the residual alignment error with an oblique single-cut rotation osteotomy using 15 complex bone deformations. The single-cut approach was not feasible in 5 cases, whereas the ODCRO procedure was feasible in all cases. The residual alignment error was smaller for the ODCRO than for the single-cut approach except for one case. In a subset for length reconstruction, the length error of 7.3-21.3 mm was restored to 0.0 mm in 4 of 5 cases, although at the cost of an increased transverse translation. The proposed method renders planning an ODCRO feasible and helps restoring bone alignment and lengthening better than an oblique single-cut rotation osteotomy. Awareness of the challenges and possibilities in preoperative planning of an ODCRO will be of value for future alignment surgery and for patients.

Carpal Kinematics in Madelung Deformity.

PURPOSE: Various skeletal and soft tissue abnormalities have been identified in Madelung deformity and have been hypothesized to play a causal role in its progressive symptomatology; however, our pathological understanding of these changes remains limited. In this study, we biomechanically assessed the Madelung deformity wrist, using 4-dimensional computed tomography imaging. METHODS: Nine Madelung deformity wrists (5 patients; age, 24 ± 5 y) and 18 healthy wrists (9 volunteers; age, 28 ± 3 y) underwent 4-dimensional imaging during flexion-extension motion and radioulnar deviation. Carpal kinematics and radiocarpal joint parameters were quantified and compared. RESULTS: In Madelung deformity wrists, significantly decreased rotation was seen in the lunate (-4.6°) and the triquetrum (-4.8°) during flexion-extension motion. During radioulnar deviation, significant decreases were visible in lunate bone translation (-0.7 mm), triquetrum bone translation (-0.6 mm), and triquetrum bone rotation (-1.9°). Patients had significantly decreased articulating surface areas of the scaphoid (1.4 ± 0.2 cm2 versus 1.6 ± 0.2 cm2) and lunate (1.2 ± 0.4 cm2 versus 1.5 ± 0.3 cm2) fossa, and significantly increased radioscaphoid (1.3 ± 0.1 mm versus 1.2 ± 0.1 mm) and radiolunate (1.6 ± 0.2 mm versus 1.3 ± 0.3 mm) joint space thicknesses. CONCLUSIONS: There is a decreased mobility of the lunate and triquetrum bones in Madelung deformity. CLINICAL RELEVANCE: Four-dimensional imaging could be used in future studies that investigate the effect of surgical ligament release on carpal kinematics and subsequent wrist mobility.

Mapping Solute Clearance From the Mouse Hippocampus Using a 3D Imaging Cryomicrotome.

The hippocampus is susceptible to protein aggregation in neurodegenerative diseases such as Alzheimer's disease. This protein accumulation is partially attributed to an impaired clearance; however, the removal pathways for fluids and waste products are not fully understood. The aim of this study was therefore to map the clearance pathways from the mouse brain. A mixture of two fluorescently labeled tracers with different molecular weights was infused into the hippocampus. A small subset of mice (n = 3) was sacrificed directly after an infusion period of 10 min to determine dispersion of the tracer due to the infusion, while another group was sacrificed after spreading of the tracers for an additional 80 min (n = 7). Upon sacrifice, mice were frozen and sectioned as a whole by the use of a custom-built automated imaging cryomicrotome. Detailed 3D reconstructions were created to map the tracer spreading. We observed that tracers distributed over the hippocampus and entered adjacent brain structures, such as the cortex and cerebroventricular system. An important clearance pathway was found along the ventral part of the hippocampus and its bordering interpeduncular cistern. From there, tracers left the brain via the subarachnoid spaces in the directions of both the nose and the spinal cord. Although both tracers followed the same route, the small tracer distributed further, implying a major role for diffusion in addition to convection. Taken together, these results reveal an important clearance pathway of solutes from the hippocampus.

The influence of soft tissue artifacts on multi-segment foot kinematics.

Movement of skin markers with respect to their underlying bone (i.e. soft tissue artifacts (STAs)) might corrupt the accuracy of marker-based movement analyses. This study aims to quantify STAs in 3D for foot markers and their effect on multi-segment foot kinematics as calculated by the Oxford and Rizzoli Foot Models (OFM, RFM). Fifteen subjects with asymptomatic feet were seated on a custom-made loading device on a computed tomography (CT) table, with a combined OFM and RFM marker set on their right foot. One unloaded reference CT-scan with neutral foot position was performed, followed by 9 loaded CT-scans at different foot positions. The 3D-displacement (i.e. STA) of each marker in the underlying bone coordinate system between the reference scan and other scans was calculated. Subsequently, segment orientations and joint angles were calculated from the marker positions according to OFM and RFM definitions with and without STAs. The differences in degrees were defined as the errors caused by the marker displacements. Markers on the lateral malleolus and proximally on the posterior aspect of the calcaneus showed the largest STAs. The hindfoot-shank joint angle was most affected by STAs in the most extreme foot position (40° plantar flexion) in the sagittal plane for RFM (mean: 6.7°, max: 11.8°) and the transverse plane for OFM (mean: 3.9°, max: 6.8°). This study showed that STAs introduce clinically relevant errors in multi-segment foot kinematics. Moreover, it identified marker locations that are most affected by STAs, suggesting that their use within multi-segment foot models should be reconsidered.

Patient-specific plate for navigation and fixation of the distal radius: a case series.

PURPOSE: Corrective osteotomy of a malunited distal radius conventionally relies on 2D imaging techniques for alignment planning and evaluation. However, this approach results in suboptimal bone repositioning, which is associated with poor patient outcomes. In this case series, we evaluate the use of novel patient-specific plates (PSPs), which feature navigation and fixation of bone segments as preoperatively planned in 3D. METHODS: Ten participants with distal radius malunion underwent CT scans for preoperative alignment planning. Patient-specific guides and plates were designed, 3D-printed, and sterilized for use in corrective surgery of the distal radius. Pre- and postoperative results were compared in regard to clinical, functional, and radiographic outcomes. RESULTS: The application of a PSP was successful in 7 of the 10 cases. After treatment, the residual alignment error was reduced by approximately 50% compared with conventional treatment. The use of PSPs reduced pain significantly. Pre- and postoperative results were pooled and demonstrated significant correlations between: (1) pain and malpositioning, (2) the range of pro- and supination motion, the MHOQ score, the EQ-5D-5L score and dorsovolar angulation, and (3) MHOQ score and proximodistal translation. CONCLUSION: The correlation between malalignment and MHOQ score, EQ-5D-5L score, pain, and range of motion shows that alignment should be restored as well as possible. Compared to the conventional approach, which relies on 2D imaging techniques, corrective osteotomy based on 3D preoperative planning and intraoperative fixation with a PSP has been shown to improve bone alignment and reduce pain. LEVEL OF EVIDENCE: IV.

Accuracy of cup placement in total hip arthroplasty by means of a mechanical positioning device: a comprehensive cadaveric 3d analysis of 16 specimens.

INTRODUCTION: We tested whether a mechanical device (such as Hipsecure) to pinpoint the anterior pelvic plane (APP) as a guide can improve acetabular cup placement. To assess accuracy we asked: (1) is the APP an effective guide to position acetabular cup placement within acceptable ° of divergence from the optimal 40° inclination and 15° anteversion; (2) could a mechanical device increase the number of acetabular cup placements within Lewinnek's safe zone (i.e. inclination 30° to 50°; anteversion 5° to 25°)? METHODS: 16 cadaveric specimens were used to assess the 3D surgical success of using a mechanical device APP to guide acetabular cup placement along the APP. We used the Hipsecure mechanical device to implant acetabular cups at 40° inclination and 15° anteversion. Subequently, all cadaveric specimens with implants were scanned with a CT and 3D models were created of the pelvis and acetabular cups to assess the outcome in terms of Lewinnek's safe zones. RESULTS: The mean inclination of the 16 implants was 40.6° (95% CI, 37.7-43.4) and the mean anteversion angle was 13.4° (95% CI, 10.7-16.1). All 16 cup placements were within Lewinnek's safe zone for inclination (between 30° and 50°) and all but 2 were within Lewinnek's safe zone for anteversion (between 5° and 25°). CONCLUSION: In cadaveric specimens, the use of a mechanical device and the APP as a guide for acetabular cup placement resulted in good positioning with respect to both of Lewinnek's safe zones.

Expression and Retention of Thymidine Phosphorylase in Cultured Reticulocytes as a Novel Treatment for MNGIE.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal metabolic disorder caused by thymidine phosphorylase (TP) deficiency. Successful therapeutic interventions for this disease rely on a means for efficient and long-lasting circulation of the TP enzyme. In this study we exploit lentiviral transduction of hematopoietic stem cells and an erythroid cell line (BEL-A) to generate reticulocytes that contain active TP. Significant loss of overexpressed TP during erythroid differentiation can be reduced by addition of the ubiquitination inhibitor MG132. However, the ubiquitination sites are located in the substrate binding site in human TP, and their removal abolished enzyme activity. Examination of the TP structure and mechanism suggested that these sites are only exposed in the absence of substrate. We show that supplementation of culture media with thymidine during differentiation reduces enzyme degradation, doubling the amount of TP retained in reticulocytes. This study provides proof of principle that therapeutic reticulocytes expressing TP can be generated in vitro and that ubiquitin-mediated degradation can be subverted through masking ubiquitination sites to ensure retention of human TP in reticulocytes following erythroid differentiation.

Accuracy of manual and automatic placement of an anatomical coordinate system for the full or partial radius in 3D space.

Accurate placement of a coordinate system on the radius is important to quantitatively report 3D surgical planning parameters or joint kinematics using 4D imaging techniques. In clinical practice, the scanned length of the radial shaft varies among scanning protocols and scientific studies. The error in positioning a radial coordinate system using a partially scanned radius is unknown. This study investigates whether the imaged length of the radius significantly affects the positioning of the coordinate system. For different lengths of the radius, the error of positioning a coordinate system was determined when placed automatically or manually. A total of 85 healthy radii were systematically shortened until 10% of the distal radius remained. Coordinate systems were placed automatically and manually at each shortening step. A linear mixed model was used to associate the positioning error with the length of the radial shaft. The accuracy and precision of radial coordinate system placement were compared between automatic and manual placement. For automatic placement of the radial coordinate system, an increasing positioning error was associated with an increased shortening of the radius (P = < 0.001). Automatic placement is superior to manual placement; however, if less than 20% of the radial shaft length remains, manual placement is more accurate.