Muscle forces acting on the greater trochanter lead to a dorsal warping of the apophyseal growth plate.

The apophyseal growth plate of the greater trochanter, unlike most other growth plates of the human body, exhibits a curved morphology that results in a divergent pattern resembling an open crocodile mouth on plain antero-posterior radiographs. To quantify the angular alignment of the growth plate and to draw conclusions about the function of the muscles surrounding it, we analyzed 57 MRI images of 51 children and adolescents aged 3-17 years and of six adults aged 18-52 years. We measured the angulation of the plate relative to the horizontal plane (AY angle) and the trajectories of the muscles attaching to the greater trochanter of the proximal femur. From anterior to posterior, the AY angle shows a decrease of 33.44°. In the anterior third, the cartilage is angled at a mean of 51.64°, and in the posterior third, the mean angulation is 18.6°. This indicates that the cartilage in the anterior region of the greater trochanteric apophysis is subject to more vertically oriented force vectors compared to the posterior region, as the growth plates align perpendicular to the force vectors acting on them. Combining the measured muscle trajectories with the physiological cross-sectional areas (PCSA) available from the literature revealed that, in addition to the known internal and external lateral traction ligament systems, a third, dorsally located traction ligament system exists that may be responsible for the dorsal deformation of the AY angle.

The Effectiveness of Growth Modulation Using Tension Band Plates in Children With Achondroplasia in Comparison to Children With Idiopathic Frontal Axial Deformities of the Knee.

BACKGROUND: Achondroplasia is the most common form of rhizomelic dwarfism. Aside from disproportionally short extremities, frontal knee malalignments are common. We assessed the effectiveness of guided growth via tension band plates in children with achondroplasia in comparison to patients with idiopathic knee deformities using radiography. METHODS: Twenty children with achondroplasia (8 valgus/31 varus knees) and 35 children with idiopathic knee malalignments (53 valgus/12 varus knees) which underwent temporary hemiepiphysiodesis at the distal femur and/or proximal tibia were retrospectively compared. Radiographic outcomes (mechanical lateral distal femoral angle, medial proximal tibial angle, and mechanical axis deviation) were compared before surgery and plate removal. Correction rates according to plate location were compared as change per implant duration and per growth in leg length. RESULTS: Achondroplasia patients were younger (9±2 vs.12±2 y), femoral and tibial growth rate was 43.3% and 48.5% lower and implant duration lasted longer: 36.9±8.9 months in valgus knees and 23.0±14.3 months in varus knees versus 13.4±7.9 months in idiopathic valgus and 11.7±4.6 months in idiopathic varus knees. Significant improvements in joint orientation angles and mechanical axis deviation were achieved but femoral and tibial plates achieved slower correction per months in achondroplasia (P≤0.031). When normalized to bone growth, the rate of correction in joint orientation angles was no longer significantly different for the femur (P=0.241), with a trend for slower correction in the tibia (P=0.066). The corrections in MAD per leg growth (mm/mm) remained smaller (P=0.001). In achondroplasia, older age correlated with slower MAD correction (r=-0.36, P=0.022), femoral plates corrected faster than tibial (P=0.024) and treatment of valgus was less successful than varus involving longer treatments (P=0.009). More complications occurred in achondroplastic knees (P=0.012). CONCLUSIONS: Skeletally immature patients with achondroplasia can benefit from growth modulations, but they need longer treatments and face more complications. Their slower growth does not solely determine the more tenacious success. LEVEL OF EVIDENCE: Therapeutic Level III-case-control study.

Ultrasound supports clinical decision-making in determining the Sanders' skeletal maturity score of the hand.

PURPOSE: The Sanders Scoring System has revolutionized the way we assess the remaining growth potential of the skeleton. However, because it involves radiation exposure, it must be used with caution in children. The purpose of the study was to evaluate whether the Sanders skeletal maturity score (SMS) could be accurately determined using ultrasound (U). METHODS: We took radiographs (R) of the hand and performed U of the thumb and index finger in 115 patients between six and 19 years of age who were undergoing treatment for scoliosis or limb deformities. Paediatric orthopaedic surgeons, a paediatrician, and a paediatric radiologist were evaluated the blinded images. Those classified images are based on the SMS and the Thumb Ossification Composite Index (TOCI). RESULTS: Intrarater reliability was high for SMS and slightly weaker for TOCI, but still significant. Interrater reliability was clear for R and weaker for U in both staging systems. Ultimately, SMS 3 and 7 achieved the highest percentage of concordance (P) of 71.7% and 66.0%, respectively, when U was performed. Combining the clinically relevant groups of SMS 3&4 and SMS 7&8 also significantly increased peak scores (SMS 3 and 4 P = 76.7%; SMS 7 and 8 P = 79.7%). The probabilities of peak scores were significantly weaker when the TOCI score was examined. CONCLUSION: Our study shows that U can be used effectively especially to measure stages 3 and 4 and stages 7 and 8 of SMS. The U method is easy to use and therefore may offer advantages in clinical practice without the need for radiation exposure.

Hydrogel-based autologous chondrocyte implantation leads to subjective improvement levels comparable to scaffold based autologous chondrocyte implantation.

PURPOSE: Scaffold-based autologous chondrocyte implantation is a well-established treatment for cartilage defects in the knee joint. Hydrogel-based autologous chondrocyte implantation using an in situ polymerizable biomaterial is a relatively new treatment option for arthroscopic cartilage defects. It is therefore important to determine if there are significant differences in the outcomes. The aim of this study is to compare the outcomes (using subjective parameters) of hydrogel-based autologous chondrocyte implantation (NOVOCART® Inject) with the outcomes of scaffold based autologous chondrocyte Implantation (NOVOCART® 3D) using biphasic collagen scaffold. METHODS: The data of 50 patients, which were paired with 25 patients in each treatment group, was analyzed. The main parameters used for matching were gender, number of defects and localization. Both groups were compared based on Visual Analogue Scale (VAS) and subjective IKDC scores, both of which were examined pre-operatively and after 6, 12 and 24 months. RESULTS: Significant benefits in both VAS and IKDC scores after 2 years of follow-up in both groups were found. Comparing the groups, the results showed that in the hydrogel-based autologous chondrocyte implantation group, significant changes in IKDC scores are measurable after 6 months, while it takes 12 months until they are seen in the scaffold based autologous chondrocyte group. CONCLUSION: Hydrogel-based autologous chondrocyte and scaffold based autologous chondrocyte show comparable improvements and significant benefits to the patients' subjective well-being after a 2-year-follow-up. LEVEL OF EVIDENCE: III.

Biodegradable magnesium vs. polylactide pins for radial head fracture stabilization: a biomechanical study.

BACKGROUND: Biodegradable implants have gained increasing importance for the fixation of simple displaced radial head fractures to supersede implant removal and to minimize cartilage destruction. Commonly used polylactide pins still lead to higher rates of secondary loss of reduction compared with metal implants. Alternatively, implants made from a magnesium alloy meanwhile are available in a pin design that hypothetically could perform better than polylactide pins. Because biomechanical data of clinical applications are lacking, the goal of the present study was to biomechanically compare magnesium pins to polylactide pins using a Mason type II radial head fracture model. METHODS: Fourteen pairs of fresh-frozen human cadaver radii with a standardized Mason type II radial head fracture were stabilized either by two 2.0-mm polylactide pins (PPs) or two 2.0-mm magnesium pins (MPs). Biomechanical in vitro testing was conducted as 10 cycles of static loading at 0.1 Hz axially and transversally between 10 and 50 N. Afterward, loosening was tested by dynamic load changes at 4 Hz up to 100,000 cycles. Early fracture displacement was measured after 10,000 cycles. Afterward, maximum loads were raised every 10,000 cycles by 15 N until construct failure, which was defined as fracture displacement ≥2 mm. RESULTS: MP osteosynthesis showed a tendency toward higher primary stability on both axial (MP: 0.19 kN/mm, PP: 0.11 kN/mm; P = .068) and transversal loading (MP: 0.11 kN/mm, PP: 0.10 kN/mm; P = .068). Early fracture displacement was significantly higher following PP osteosynthesis (MP: 0.3 mm, PP: 0.7 mm; P = .030). The superiority of MP was also significant during cyclic loading, represented in a higher failure cycle (MP: 30,684, PP: 5113; P = .009) and in higher failure loads (MP: 95 N, PP: 50 N; P = .024). CONCLUSION: According to our findings, in simple radial head fractures, osteosynthesis with magnesium pins show superior biomechanical properties compared with fractures treated by polylactide pins. Prospective investigations should follow to evaluate clinical outcomes and resorption behavior.

Low-profile double plating of unstable osteoporotic olecranon fractures: a biomechanical comparative study.

BACKGROUND: In the treatment of unstable olecranon fractures, anatomically preshaped locking plates exhibit superior biomechanical results compared with tension band wiring. However, posterior plating (PP) still is accompanied by high rates of plate removal because of soft-tissue irritation and discomfort. Meanwhile, low-profile plates precontoured for collateral double plating (DP) are available and enable muscular soft-tissue coverage combined with angular-stable fixation. The goal of this study was to biomechanically compare PP with collateral DP for osteosynthesis of unstable osteoporotic fractures. METHODS: A comminuted displaced Mayo type IIB fracture was created in 8 osteoporotic pairs of fresh-frozen human cadaveric elbows. Pair-wise angular stable fixation was performed by either collateral DP or PP. Biomechanical testing was conducted as a pulling force to the triceps tendon in 90° of elbow flexion. Cyclical load changes between 10 and 300 N were applied at 4 Hz for 50,000 cycles. Afterward, the maximum load was raised by 0.02 N/cycle until construct failure, which was defined as displacement > 2 mm. Besides failure cycles and failure loads, modes of failure were analyzed. RESULTS: Following DP, a median endurance of 65,370 cycles (range, 2-83,121 cycles) was recorded, which showed no significant difference compared with PP, with 69,311 cycles (range, 150-81,938 cycles) (P = .263). Failure load showed comparable results as well, with 601 N (range, 300-949 N) after DP and 663 N (range, 300-933 N) after PP (P = .237). All PP constructs and 3 of 8 DP constructs failed by proximal fragment cutout, whereas 5 of 8 DP constructs failed by bony triceps avulsion. CONCLUSION: Angular-stable DP showed comparable biomechanical stability to PP in unstable osteoporotic olecranon fractures under high-cycle loading conditions. Failure due to bony triceps avulsion following DP requires further clinical and biomechanical investigation, for example, on suture augmentation or different screw configurations.

Injury patterns following simple elbow dislocation: radiological analysis implies existence of a pure valgus dislocation mechanism.

INTRODUCTION: The aim of the present study was to analyze the injury pattern and thus the dislocation mechanism after simple elbow dislocation using radiographs and magnetic resonance imaging (MRI) data sets. MATERIALS AND METHODS: The MRI data sets of 64 patients with a mean age of 44 years (18-77 years) were analyzed retrospectively. The inclusion criteria for the study were (1) radiograph with confirmed simple elbow dislocation, (2) low-energy trauma, (3) MRI of the affected elbow ≤ 3 weeks after trauma. The dislocation direction was determined using radiographs. The integrity of the lateral collateral ligament complex (LCLC), common extensor origin (CEO), anterior capsule (AC), medial collateral ligament (MCL), and common flexor origin (CFO) as well as the joint congruity were assessed based on MRI. RESULTS: 34 patients (53%) had a posterolateral, 26 patients (41%) a posterior, and 4 patients (6%) a posteromedial dislocation. LCLC and AC were affected in 64 out of 64 patients (100%). MCL was affected in 58 patients (91%). CEO were affected in 25 patients (39%) and the CFO in 20 patients (31%). In 11 patients (17%) the injury pattern was more pronounced medially than laterally (MCL, CFO, LCLC), with 2 of these patients exhibiting only a partial LCLC tear. All cases with joint incongruency (n = 12, 19%) showed CEO and/or CFO involvement. CONCLUSIONS: Simple elbow dislocation leads to a very heterogeneous spectrum of soft tissue injury pattern. A small proportion of patients showed medially pronounced injury patterns. These findings strongly indicate existence of a "reversed Horii circle" with an underlying valgus mechanism (medial force induction) originating and continuing from medial to anterior.

The acromioclavicular ligament shows an early and dynamic healing response following acute traumatic rupture.

PURPOSE: Symptomatic horizontal instability is clinically relevant following acute acromioclavicular joint dislocations. However, the intrinsic healing response is poorly understood. The present study sought to investigate time-dependent healing responses of the human acromioclavicular ligament following acute traumatic rupture. METHODS: Biopsies of the acromioclavicular ligament were obtained from patients undergoing surgical treatment for acute acromioclavicular joint dislocations. Specimens were stratified by time between trauma and surgery: group 1, 0-7 days (n = 5); group 2, 8-14 days (n = 6); and group 3, 15-21 days (n = 4). Time-dependent changes in cellularity, collagen (type 1 and 3) concentration, and histomorphological appearance were evaluated for the rupture and intact zone of the acromioclavicular ligament. RESULTS: Group 1 was characterized by cellular activation and early inflammatory response. The rupture zone exhibited a significantly higher count of CD68-positive cells than the intact zone (15.2 vs 7.4; P ≤ 0.05). Consistently, synovialization of the rupture end was observed. Within the second week, the rupture zone was subject to proliferation showing more fibroblast-like cells than the intact zone (66.8 vs 43.8; P ≤ 0.05) and a peak of collagen type 3 expression (group 1: 2.2 ± 0.38, group 2: 3.2 ± 0.18, group 3: 2.8 ± 0.57; P ≤ 0.05). Signs of consolidation and early remodeling were seen in the third week. CONCLUSIONS: The acromioclavicular ligament exhibits early and dynamic healing responses following acute traumatic rupture. Our histological findings suggest that surgical treatment of acute ACJ dislocations should be performed as early as possible within a timeframe of 1 week after trauma to exploit the utmost biological healing potential. Prospective clinical studies are warranted to investigate whether early surgical treatment of ACJ dislocations translates into clinical benefits.

Biomechanical comparison of biodegradable magnesium screws and titanium screws for operative stabilization of displaced capitellar fractures.

BACKGROUND: Displaced fractures of the humeral capitellum are commonly treated operatively and fixed by titanium screws (TSs) either directly or indirectly. In the case of direct transcartilaginous fixation, biodegradable screws with the ability to be countersunk can be favorable regarding implant impingement and cartilage destruction. Hence, the goal of this study was to biomechanically compare headless compression screws made from titanium with a biodegradable equivalent made from a magnesium alloy. METHODS: This biomechanical in vitro study was conducted on 13 pairs of fresh-frozen human cadaveric humeri, in which a standardized Bryan-Morrey type I fracture was fixed using 2 magnesium screws (MSs) or 2 TSs. First, construct stiffness was measured during 10 cycles of static loading between 10 and 50 N. Second, continuous loading was applied at 4 Hz between 10 and 50 N, increasing the maximum load every 10,000 cycles by 25 N until construct failure occurred. This was defined by fragment displacement >3 mm. RESULTS: Comparison of the 2 screw types showed no differences related to construct stiffness (0.50 ± 0.25 kN/mm in MS group and 0.47 ± 0.13 kN/mm in TS group, P = .701), failure cycle (43,944 ± 21,625 and 41,202 ± 16,457, respectively; P = .701), and load to failure (152 ± 53 N and 150 ± 42 N, respectively; P = .915). CONCLUSION: Biomechanical comparison showed that simple capitellar fractures are equally stabilized by headless compression screws made from titanium or a biodegradable magnesium alloy. Therefore, in view of the advantages of biodegradable implants for transcartilaginous fracture stabilization, their clinical application should be considered and evaluated.

SOX9 Knockout Induces Polyploidy and Changes Sensitivity to Tumor Treatment Strategies in a Chondrosarcoma Cell Line.

As most chemotherapeutic drugs are ineffective in the treatment of chondrosarcoma, we studied the expression pattern and function of SOX9, the master transcription factor for chondrogenesis, in chondrosarcoma, to understand the basic molecular principles needed for engineering new targeted therapies. Our study shows an increase in SOX9 expression in chondrosarcoma compared to normal cartilage, but a decrease when the tumors are finally defined as dedifferentiated chondrosarcoma (DDCS). In DDCS, SOX9 is almost completely absent in the non-chondroid, dedifferentiated compartments. CRISPR/Cas9-mediated knockout of SOX9 in a human chondrosarcoma cell line (HTB94) results in reduced proliferation, clonogenicity and migration, accompanied by an inability to activate MMP13. In contrast, adhesion, apoptosis and polyploidy formation are favored after SOX9 deletion, probably involving BCL2 and survivin. The siRNA-mediated SOX9 knockdown partially confirmed these results, suggesting the need for a certain SOX9 threshold for particular cancer-related events. To increase the efficacy of chondrosarcoma therapies, potential therapeutic approaches were analyzed in SOX9 knockout cells. Here, we found an increased impact of doxorubicin, but a reduced sensitivity for oncolytic virus treatment. Our observations present novel insight into the role of SOX9 in chondrosarcoma biology and could thereby help to overcome the obstacle of drug resistance and limited therapy options.

Recombinant Human Bone Morphogenetic Protein 7 Exerts Osteo-Catabolic Effects on Bone Grafts That Outweigh Its Osteo-Anabolic Capacity.

This study aimed to investigate the effects of recombinant human bone morphogenetic protein (rhBMP-7) on human cancellous bone grafts (BGs) while differentiating between anabolic and catabolic events. Human BGs alone or supplemented with rhBMP-7 were harvested 14 weeks after subcutaneous implantation into NOD/Scid mice, and studied via micro-CT, histomorphometry, immunohistochemistry and flow cytometry. Immunohistochemical staining for human-specific proteins made it possible to differentiate between grafted human bone and newly formed murine bone. Only BGs implanted with rhBMP-7 formed an ossicle containing a functional hematopoietic compartment. The total ossicle volume in the BMP+ group was higher than in the BMP- group (835 mm3 vs. 365 mm3, respectively, p < 0.001). The BMP+ group showed larger BM spaces (0.47 mm vs. 0.28 mm, p = 0.002) and lower bone volume-to-total volume ratio (31% vs. 47%, p = 0.002). Immunohistochemical staining for human-specific proteins confirmed a higher ratio of newly formed bone area (murine) to total area (0.12 vs. 0.001, p < 0.001) in the BMP+ group, while the ratio of grafted bone (human) area to total area was smaller (0.14 vs. 0.34, p = 0.004). The results demonstrate that rhBMP-7 induces BG resorption at a higher rate than new bone formation while creating a haematopoietic niche. Clinicians therefore need to consider the net catabolic effect when rhBMP-7 is used with BGs. Overall, this model indicates its promising application to further decipher BMPs action on BGs and its potential in complex bone tissue regeneration.

Patients under 4 years old treated with overhead extension for isolated femoral fractures - lessons learned concerning parents' satisfaction.

BACKGROUND: Conservative options are the standard for treatment of femoral fractures for patients under the age of 4 years. We investigated possible factors influencing the satisfaction of the parents in order to improve their experience. PATIENTS: We analyzed 42 cases of children under the age of 4 years treated with overhead extension therapy (OHE) for femoral fracture. METHODS: Our protocol requires transition to spica cast treatment (SCT) and discharge from the hospital after the initial 10-day OHE. X-rays were analyzed for fracture healing. A pseudonymized questionnaire was sent to the parents in order to evaluate their experiences during the treatment. RESULTS: The nature of the fracture was explained to 73.3% of the parents in a way that was "understandable and in detail". However, 23.3% stated that "many questions were not answered". Seventy percent of parents noticed behavioral abnormalities during treatment, and 63.3% reported treatment-specific problems. Additionally, 86.7% of parents were satisfied with the therapy outcome, 80% were content with the type of therapy, and 73.3% would choose OHE again. We found a high Spearman correlation between general satisfaction and parents who felt well informed. There was also a strong correlation between high general satisfaction and the opportunity for any problems to be discussed and addressed during the medical rounds. DISCUSSION: The reasons for nonsatisfaction were primarily due to communication problems. CONCLUSION: Thorough evaluation during medical rounds, communication with healthcare professionals and care provided by the nurses affects the contentment of the families significantly.

Immune system augmentation via humanization using stem/progenitor cells and bioengineering in a breast cancer model study.

Despite significant advances, most current in vivo models fail to fully recapitulate the biological processes that occur in humans. Here we aimed to develop an advanced humanized model with features of an organ bone by providing different bone tissue cellular compartments including preosteoblasts, mesenchymal stem/stromal (MSCs), endothelial and hematopoietic cells in an engineered microenvironment. The bone compartment was generated by culturing the human MSCs, umbilical vein endothelial cells with gelatin methacryloyl hydrogels in the center of a melt-electrospun polycaprolactone tubular scaffolds, which were seeded with human preosteoblasts. The tissue engineered bone (TEB) was subcutaneously implanted into the NSG mice and formed a morphologically and functionally organ bone. Mice were further humanized through the tail vein injection of human cord blood derived CD34+ cells, which then populated in the mouse bone marrow, spleen and humanized TEB (hTEB). 11 weeks after CD34+ transplantation, metastatic breast cancer cells (MDA-MB-231BO) were orthotopically injected. Cancer cell injection resulted in the formation of a primary tumor and metastasis to the hTEB and mouse organs. Less frequent metastasis and lower tumor burden were observed in hematochimeric mice, suggesting an immune-mediated response against the breast cancer cells. Overall, our results demonstrate the efficacy of tissue engineering approaches to study species-specific cancer-bone interactions. Further studies using genetically modified hematopoietic stem cells and bioengineered microenvironments will enable us to address the specific roles of signaling molecules regulating hematopoietic niches and cancer metastasis in vivo.

Tissue engineering and regenerative medicine in musculoskeletal oncology.

Currently used surgical techniques to reconstruct tissue defects after resection of musculoskeletal tumours are associated with high complication rates. This drives a strong demand for innovative therapeutic concepts that are able to improve the clinical outcomes of patients suffering from bone and soft tissue tumours. Tissue engineering and regenerative medicine (TE&RM) provides a technology platform based on biochemical, molecular, cellular and biomaterials modules to selectively direct tissue healing processes for improved defect regeneration. At the same time, precautionary measures have to be taken when these instruments are used in cancer patients to prevent any promotion of tumour growth or metastatic spread. On the other hand, several innovative TE&RM tools are being developed such as multi-functionalized biomaterials, drug-delivering nanomaterials or genetically engineered stem cells that per se have the potential to mediate anti-cancer effects, act synergistically with currently used chemotherapeutics and/or radiotherapy regimens and reduce their side effects. Recently, scientists became conscious that TE&RM strategies may not only be utilized to advance contemporary tissue reconstruction techniques but also to develop personalized diagnostic tools and clinically relevant disease models for cancer patients. Eventually, prospective randomized clinical trials combined with comparative outcome analyses are a conditio sine qua non to shape the benefits of personalized regenerative therapies for the standardized management of patients with musculoskeletal tumours.

Presence of rotational errors in long leg radiographs after total knee arthroplasty and impact on measured lower limb and component alignment.

PURPOSE: Rotation of the lower limb in weight bearing long leg radiographs has a great impact on measured component and lower limb alignment parameters. We asked which rotational errors of long leg radiographs are present in a high volume centre and which radiological and clinical consequences arise regarding measured coronal component and lower limb alignment after total knee arthroplasty. METHODS: In 100 long leg radiographs coronal femoral and tibial component alignment and hip knee ankle angle (HKA) were measured. Present rotational errors in long leg radiographs were determined by fibular overlap and its impact on alignment parameters calculated. RESULTS: A mean internal rotation of 8.1° (9.3 SD) with a range between 36° of internal and 16° of external rotation was found in long leg radiographs. This resulted in mean differences between measurements before and after rotational correction regarding femoral and tibial component alignment and HKA of 0.6-0.8° (range 3.5° valgus and 1.6° varus error). Clinically, 11 out of 100 patients were wrongly assigned to either mal- or well-alignment (neutral mechanical alignment within ±3° varus or valgus). CONCLUSION: Surgeons should be aware of potential rotational errors in long leg radiographs after total knee arthroplasty resulting in wrong measurements. In case of rotational errors, radiographs should be repeated or rotational corrections calculated. For study purposes only radiographs after rotational correction should be accepted.

Concise review: humanized models of tumor immunology in the 21st century: convergence of cancer research and tissue engineering.

Despite positive testing in animal studies, more than 80% of novel drug candidates fail to proof their efficacy when tested in humans. This is primarily due to the use of preclinical models that are not able to recapitulate the physiological or pathological processes in humans. Hence, one of the key challenges in the field of translational medicine is to "make the model organism mouse more human." To get answers to questions that would be prognostic of outcomes in human medicine, the mouse's genome can be altered in order to create a more permissive host that allows the engraftment of human cell systems. It has been shown in the past that these strategies can improve our understanding of tumor immunology. However, the translational benefits of these platforms have still to be proven. In the 21st century, several research groups and consortia around the world take up the challenge to improve our understanding of how to humanize the animal's genetic code, its cells and, based on tissue engineering principles, its extracellular microenvironment, its tissues, or entire organs with the ultimate goal to foster the translation of new therapeutic strategies from bench to bedside. This article provides an overview of the state of the art of humanized models of tumor immunology and highlights future developments in the field such as the application of tissue engineering and regenerative medicine strategies to further enhance humanized murine model systems.

Current therapeutic strategies of heterotopic ossification--a survey amongst orthopaedic and trauma departments in Germany.

BACKGROUND: Heterotopic ossification (HO) is a complication after tissue trauma, fracture and surgery (i.e. total hip arthroplasty). Prophylaxis is the most effective therapy. If HO formations become symptomatic and limit patients' quality of life, revision surgery is indicated and is usually combined with a perioperative oral prophylaxis (NSAIDs) and/or irradiation. However, a long-term use of NSAIDs can induce gastro-intestinal or cardiac side-effects and possible bony non-unions during fracture healing. Subject of this study was to assess the current status of HO prophylaxis after injuries or fractures and to evaluate current indications and strategies for excision of symptomatic HO. METHODS: Between 2013 and 2014, a questionnaire was sent to 119 orthopaedic and trauma surgery departments in Germany. Participation was voluntary and all acquired data was given anonymously. RESULTS: The cumulative feedback rate was 71 %. Trauma and orthopaedic surgery departments in Germany recommend oral HO prophylaxis after acetabulum and femoral neck fractures, elbow dislocation, and fracture or dislocation of the radial head. Pain upon movement and an increasing loss of range of motion in the affected joint are considered to be clear indications for HO surgery. A partial removal of ROM-limiting HO formations was also considered important. The vast majority of all departments include perioperative oral HO prophylaxis and/or irradiation if surgical HO removal is planned. The choice and duration of NSAIDs is highly variable. CONCLUSION: HO is of clinical significance in current traumatology and orthopaedics. Certain fractures and injuries are prone to HO, and prophylactic measures should be taken. The respondents in this survey assessed current therapeutic strategies for HO formations similarly. These concepts are in line with the literature. However, the duration of perioperative oral HO prophylaxis varied greatly among the specialist centres. This is significant as a long-term use of NSAIDs fosters a potential risk for the patients' safety and could influence the clinical outcome. National and international guidelines need to be developed to further reduce HO rates and improve patients' safety in trauma and orthopaedic surgery.

The impact of hypoxia on mesenchymal progenitor cells of human skeletal tissue in the pathogenesis of heterotopic ossification.

PURPOSE: Mesenchymal progenitor cells (MPCs) are capable of differentiating into osteo/chondrogenic cells to contribute substantially to heterotopic ossification (HO). This study aimed to examine the impact of hypoxia on MPCs in the aetiology of HO. METHODS: MPCs from human normal and HO skeletal tissue were cultivated under normoxia and hypoxia. Gene expression of factors which have a key role in HO aetiology (BMPs, COX-1 and COX-2, etc.) were examined by real-time PCR. Tissue of both groups was analysed by immunohistochemistry. RESULTS: Under hypoxia, COX-1, -2 and SOX-9 gene expression was elevated in HO MPCs, whereas in normal muscle tissue only COX-2 was upregulated. MPCs from HO had a significantly elevated gene expression of BMP-4 and decreased expression of BMP-1 and HIF-1 under hypoxia compared to normal MPCs. Immunohistochemistry detected no significant differences between normal and HO tissue. CONCLUSIONS: Hypoxia causes an enhanced gene expression of factors, which have a key role in HO pathophysiology. A better understanding of this entity will possibly allow reducing HO rates in orthopaedic and trauma surgery.

Midterm clinical and radiological outcomes of arthrogryposis-associated clubfoot treated with the Ponseti method: a retrospective observational study and comprehensive literature review.

BACKGROUND: The treatment results of the Ponseti method for arthrogrypotic clubfoot have been described in only a few case series. Further evaluations are necessary. METHODS: Children from two German paediatric orthopaedic hospitals with arthrogryposis-associated clubfoot treated with the Ponseti method between 2004 and 2011 and who were at least five years of age at their last follow-up were retrospectively evaluated. The endpoints were the clinical foot position, necessary surgeries during the follow-up period and radiological constellations. A comprehensive literature review was conducted after a systematic literature search. RESULTS: Seventeen patients (47% with amyoplasia [AP] and 53% with distal arthrogryposis [DA]) met the inclusion criteria. Thirty-one feet were evaluated. The period between the treatment start and the last follow-up examination covered 8.9 ± 2.5 years. After the last cast removal within the initial Ponseti cast series, 74% of the clinical results were good to excellent. However, the clinical outcomes in the patients with AP were significantly worse. Overall, in 23 feet (74%), at least one major surgery at the age of 2.9 ± 2.2 years was necessary during the clinical course. Major surgeries were much more frequent on the feet of the patients with AP than with DA. Lateral X-rays showed normal age-appropriate radiological angles in 4% of the feet, hindfoot equinus in 19%, under-corrected hindfoot in 44%, under-corrected clubfoot in 26% and rocker bottom deformity in 7%. The radiological residual deformities in AP were much more severe than in DA (p = 0.042). Most of the studies reviewed (11 case series, 144 patients) reported high initial clinical correction rates, followed by high recurrence rates and the need for further surgeries. CONCLUSION: About a quarter of the arthrogrypotic patients benefited from the Ponseti therapy without further major surgery. However, the clinically observed high initial correction rate after Ponseti therapy of arthrogrypotic clubfoot was not accompanied by a correction of the bony foot position in the X-rays. The feet of the patients with DA had better outcomes than those of the patients with AP. Therefore, in outcome studies, a clear distinction between patients with AP and those with DA is necessary.

Clavicle Shaft Non-Unions-Do We Even Need Bone Grafts?

Background: The surgical treatment of bony non-unions is traditionally performed with additional bone grafts when atrophic and/or stronger implants when hypertrophic. In the case of the clavicle shaft, however, in our experience, a more controversial method where no additional bone graft is needed leads to equally good consolidation rates, independent of the non-union morphology. This method requires the meticulous anatomical reconstruction of the initial fracture and fixation according to the AO principle of relative stability. Methods: A retrospective review following the STROBE guidelines was performed on a consecutive cohort of all patients who received surgical treatment of a midshaft clavicle non-union at the Medical Center of the University of Freiburg between January 2003 and December 2023. Patients were identified using a retrospective systematical query in the Hospital Information System (HIS) using the International Statistical Classification of Diseases and Related Health Problems Version 10 (ICD-10) codes of the German Diagnosis Related Groups (G-DRG). Two groups were formed to compare the consolidation rates of patients who received additional bone grafting from the iliac crest with those of patients who did not. A 3.5 mm reconstruction LCP plate was used in all patients. Consolidation rates were evaluated using follow-up radiographs and outcomes after material removal with a mean follow-up of 31.5 ± 44.3 months (range 0-196). Results: Final data included 50 patients, predominantly male (29:21); age: 46.0 ± 13.0 years, BMI 26.1 ± 3.7. Autologous bone grafts from the iliac crest were used in 38.0% (n = 19), while no bone addition was used in 62.0% (n = 30). Six patients were lost to follow-up. Radiological consolidation was documented after a mean of 15.1 ± 8.0 months for the remaining 44 patients. Consolidation rates were 94.4% (n = 17) in patients for whom additional bone grafting was used and 96.2% (n = 25) in patients for whom no graft was used. There was no relevant difference in the percentage of atrophic or hypertrophic non-unions between both groups (p = 0.2425). Differences between groups in the rate of consolidation were not significant (p = 0.7890). The complication rate was low, with 4.5% (n = 2). Conclusions: Independent of the non-union morphology, non-unions of the clavicle midshaft can be treated successfully with 3.5 mm locking reconstruction plates without the use of additional bone grafting in most cases.