Epiphyseal Research Articles

Effect of the Material Properties and Knee Position to the Bone Bruise Pattern in Skeletally Mature and Immature Subjects.

A bone bruise is generated by a bony collision that could occur when the ACL is injured, and its pattern supposedly depends on the injury mechanism and level of skeletal maturity. The objective of this study was to determine the effect of material properties and knee position on the bone bruise pattern in skeletally mature and immature subjects using finite element analysis. Finite element models were created from an MR image in the sagittal plane of a skeletally mature and immature male subject. The femur and tibia were collided at 2 m/s to simulate the impact and determine the maximum principal stress. The analysis was performed at 15, 30 and 45 degrees of knee flexion, and neutral, 10 mm anterior and posterior translated position at each flexion angle. Although high stress was distributed toward the metaphysis area in the mature model, the stress did not cross the growth plate in the immature model. The size of the stress area was larger in the mature model than those in the immature model. The location of the stress area was dependent on the joint position as well as Young's modulus of cartilage and trabecular bone. Thus, the bone bruise pattern was affected by the knee position and tissue quality. In conclusion, although the bone bruise distribution was generally called footprint of the injury, the combined evaluation of the quality of the structure and the bone bruise distribution is necessary for properly diagnosing tissue injury based on the MR imaging.

Fibronectin isoforms promote postnatal skeletal development

Fibronectin (FN) is a ubiquitous extracellular matrix glycoprotein essential for the development of various tissues. Mutations in FN cause a unique form of spondylometaphyseal dysplasia, emphasizing its importance in cartilage and bone development. However, the relevance and functional role of FN during skeletal development has remained elusive. To address these aspects, we have generated conditional knockout mouse models targeting the cellular FN isoform in cartilage (cFNKO), the plasma FN isoform in hepatocytes (pFNKO), and both isoforms together in a double knockout (FNdKO). We used these mice to determine the relevance of the two principal FN isoforms in skeletal development from postnatal day one to the adult stage at two months.We identified a distinct topological FN deposition pattern in the mouse limb during different gestational and postnatal skeletal development phases, with prominent levels at the resting and hypertrophic chondrocyte zones and in the trabecular bone. Cartilage-specific cFN emerged as the predominant isoform in the growth plate, whereas circulating pFN remained excluded from the growth plate and confined to the primary and secondary ossification centers. Deleting either isoform independently (cFNKO or pFNKO) yielded only relatively subtle changes in the analyzed skeletal parameters. However, the double knockout of cFN in the growth plate and pFN in the circulation of the FNdKO mice significantly reduced postnatal body weight, body length, and bone length. Micro-CT analysis of the adult bone microarchitecture in FNdKO mice exposed substantial reductions in trabecular bone parameters and bone mineral density. The mice also showed elevated bone marrow adiposity. Analysis of chondrogenesis in FNdKO mice demonstrated changes in the resting, proliferating and hypertrophic growth plate zones, consistent alterations in chondrogenic markers such as collagen type II and X, decreased apoptosis of hypertrophic chondrocytes, and downregulation of bone formation markers. Transforming growth factor-β1 and downstream phospho-AKT levels were significantly lower in the FNdKO than in the control mice, revealing a crucial FN-mediated regulatory pathway in chondrogenesis and bone formation.In conclusion, the data demonstrate that FN is essential for chondrogenesis and bone development. Even though cFN and pFN act in different regions of the bone, both FN isoforms are required for the regulation of chondrogenesis, cartilage maturation, trabecular bone formation, and overall skeletal growth.

Sustained release of MAPK14-targeting siRNA from polyelectrolyte complex hydrogels mitigates MSC osteogenesis in vitro with potential application in growth plate injury.

The growth plate is a cartilage structure at the end of long bones which mediates growth in children. When fractured, the formation of bony repair tissue known as a "bony bar" can occur and cause limb deformities. There are currently no effective clinical solutions for the prevention of the bony bar formation or regeneration of healthy growth plate cartilage after a fracture. This study employs previously developed alginate/chitosan polyelectrolyte complex (PEC) hydrogels as a sustained release vehicle for the delivery of short-interfering RNA (siRNA). Specifically, the siRNA targets the p38-MAPK pathway in mesenchymal stem cells (MSCs) to prevent their osteogenic differentiation. In vitro experimental findings show sustained release of siRNA from the hydrogels for 6 months. Flow cytometry and confocal imaging indicate that the hydrogels release siRNA to effectively knockdown GFP expression over a sustained period. MAPK-14 targeting siRNA was used to knockdown the expression of MAPK-14 and correspondingly decrease the expression of other osteogenic genes in MSCs in vitro over the span of 21 days. These hydrogels were used in a rat model of growth plate injury to determine whether siMAPK-14 released from the gels could inhibit bony bar formation. No significant reduction of bony bar formation was seen in vivo at the one concentration of siRNA examined. This PEC hydrogel represents a significant advancement for siRNA sustained delivery, and presents an interesting potential therapeutic delivery system for growth plate injuries and other regenerative medicine applications.

Electrochemical and aging model of li-ion batteries and estimation of total number of cycles during the lifecycle of the battery

Fast charging is a critical factor for the widespread adoption of electric vehicles (EVs), yet it poses challenges to the durability of lithium-ion batteries (LiBs). This study develops an aging model for a 10 Ah LiB cell using COMSOL Multiphysics, integrating a one-dimensional electrochemical model with a zero-dimensional thermal model. The model is constructed using cell design and electrochemical parameters derived from existing literature, tailored to the specific electrode and electrolyte materials utilized in this study. Key aging phenomena, such as the Solid Electrolyte Interface (SEI) growth and lithium plating, are embedded within the model to simulate the aging patterns and the interplay between these factors across various C-rates and temperatures. Simulation results suggest that while higher charging rates can reduce charging time, they also lead to increased degradation, with lithium plating becoming more severe at these elevated rates. The model also indicates that temperature management during cell operation can influence cycle life, with strategic temperature increases potentially mitigating some negative effects of fast charging. The study also explores the concept of total charging time as an alternative metric for battery wear, examining its relationship with the charging current profile and temperature. Results indicate that while fast charging offers convenience, it significantly impacts cycle life, underscoring the need for optimized charging strategies. The insights from this work enhance the understanding of Li-ion cell aging mechanisms, shedding light on the complex trade-offs between charging speed, temperature management, and lifespan. This contributes to the development of more sophisticated battery management systems and charging protocols that aim to extend the operational life of LiBs while accommodating the demands of fast charging.

Medial femoral condyleOCD (osteochondritis dissecans): correlation between imaging and arthroscopy.

Osteochondritis dissecans (OCD) describes a pathologic condition centered at the osteochondral junction that may result in an unstable subchondral fragment (progeny), disruption of the overlying cartilage, which may separate from the underlying parent bone. It is one of the causes of chronic knee pain in children and young adults. The current literature on OCD lesions focuses primarily on the medial femoral condyle (MFC), but inconsistent use of terminology, particularly in the distinction of OCD lesions between skeletally immature and mature patients has created uncertainty regarding imaging workup, treatment, and long-term prognosis. This article reviews the pathophysiology of MFC OCD lesions, highlighting the role of endochondral ossification at the secondary growth plate of the immature femoral condyles, the rationale behind the imaging work-up, and key imaging findings that can distinguish between stable lesions, unstable lesions, and physiologic variants. This overview also provides a case-based review to introduce imaging correlates with the ROCK (Research in Osteochondritis of the Knee) arthroscopic classification.

A conserved regulation of cell expansion underlies notochord mechanics, spine morphogenesis, and endochondral bone lengthening.

Cell size is a key contributor to tissue morphogenesis 1 . As a notable example, growth plate hypertrophic chondrocytes use cellular biogenesis and disproportionate fluid uptake to expand 10-20 times in size to drive lengthening of endochondral bone 2,3 . Similarly, notochordal cells expand to one of the largest cell types in the developing embryo to drive axial extension 4-6 . In zebrafish, the notochord vacuolated cells undergo vacuole fusion to form a single large, fluid-filled vacuole that fills the cytoplasmic space and contributes to vacuolated cell expansion 7 . When this process goes awry, the notochord lacks sufficient hydrostatic pressure to support vertebral bone deposition resulting in adult spines with misshapen vertebral bones and scoliosis 8 . However, it remains unclear whether endochondral bone and the notochord share common genetic and cellular mechanisms for regulating cell and tissue expansion. Here, we demonstrate that the 5'-inositol phosphatase gene, inppl1a , regulates notochord expansion, spine morphogenesis, and endochondral bone lengthening in zebrafish. Furthermore, we show that inppl1a regulates notochord expansion independent of vacuole fusion, thereby genetically decoupling these processes. We demonstrate that inppl1a -dependent notochord expansion is essential to establish normal mechanical properties of the notochord to facilitate the development of a straight spine. Finally, we find that inppl1a is also important for endochondral bone lengthening in fish, as has been shown in the human INPPL1 -related endochondral bone disorder, Opsismodysplasia 9 . Overall, this work reveals a conserved mechanism of cell size regulation that influences disparate tissues critical for skeletal development and short-stature disorders.

Posttraumatic growth disturbances of the distal radius in childhood

Fractures of the distal radius in childhood are frequent but rarely lead to relevant growth disturbances. The experiences of apediatric trauma center over 15years are exemplarily presented and discussed. Osteotomies of the distal radius were selected and the clinical and radiological findings were recorded and analyzed. Posttraumatic growth disturbances were corrected in 10 cases with amedian age of 13 ½ years. In six cases an iatrogenic cause was also possible. In two cases callus distraction with secondary palmar plate osteosynthesis was used for consolidation. In eight cases primary ad hoc corrections were carried out using palmar plate osteosynthesis (six with iliac crest and two with allogeneic grafts). In five cases the distal ulnar growth plate was also addressed. During follow-up breakage of one plate was registered. After an average of 31months postoperatively, 9 children had full range of motion (ROM) and in 1 case there was an extension deficit of 10o. It is important to evaluate the cause of the mostly partially inhibiting growth disturbances to draw preventive conclusions. From a clinical perspective the visible deformity is given priority and the pain and functional limitations are less relevant. The indications for corrective surgery must include the age of the patient, remaining growth potential, size and localization of the growth plate bridge, the deformity and the individual wishes of patients and parents. In most cases afull correction is possible with palmar plate osteosynthesis and an iliac crest graft. External fixation and callus distraction is an alternative in cases where the correction is more extensive. The distal ulnar growth plate should be controlled concerning further growth potential before hardware removal.

A Systematic Review of the Optimal Management of Pediatric Distal Radius Displacement Fractures: Open Reduction and Internal Fixation Versus Cast Placement.

Distal radius fracturesare among the most common pediatric injuries, affecting thousands of children each year. These fractures often require clinical intervention to reduce displacement and ensure the proper healing of the growth plate and wrist bone. The primary objective of this comprehensive analysis is to compare the effectiveness of open reduction and internal fixation (ORIF) versus cast placement in the treatment of pediatric distal radius fractures, with the aim of identifying the optimal treatment approach. Therefore, a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted on pediatric distal radius displacement fractures using extensive database searches from 2000 to 2024 for specific keywords, ensuring transparency and reproducibility. Our findings indicate that higher displacement necessitates ORIF to minimize long-term complications and ensure better functional outcomes for pediatric patients. Rare studies comparing ORIF and cast placement are analyzed, emphasizing the advantages and limitations of each approach. The document concludes that the choice between ORIF and casting depends on factors such as fracture severity, patient's age, and specific characteristics of the injury to ensure optimal outcomes in pediatric distal radius fracture management. In conclusion, our data suggests that ORIF and cast placement each have pros and cons for pediatric distal radius fractures, with the best treatment depending on fracture specifics and patient factors, but neither method is clearly superior for long-term outcomes.

Complex ontogeny of sexual size dimorphism in a female-larger gecko: Implications of determinate growth for lizard body size and life-history evolution.

Ectothermic vertebrates such as reptiles were assumed to be indeterminate growers, which means that there is no terminal point in time or size for growth in their lifetime. In recent years, evidence for the determinate nature of growth in lizards has accumulated, necessitating a re-examination of models of their ontogeny and evolution of sexual size dimorphism (SSD). In the female-larger gecko Paroedura vazimba, we monitored post-embryonic growth over a period of 15 months. After hatching, females grew faster than males but also reached their final body size, that is, closed growth of their vertebrae, earlier than males. The closure of bone growth in females correlates with the onset of reproductive maturation. We compared this pattern with the previously minutely studied, male-larger species Paroedura picta, where we documented determinate growth as well. We propose a model to explain the evolutionary switches in the direction of SSD in lizards based on bipotential effects of ovarian hormones on growth. In this model, male growth is assumed to require no male-specific growth modifier, such as sex-limited hormonal regulators, while growth is feminized by ovarian hormones in females. Low levels of ovarian hormones can promote bone growth, but high levels associated with maturation of the reproductive organs promote senescence of bone growth plates and thus cessation of bone growth. We suggest that models on growth, life-history and evolution of body size in many lizards should acknowledge their determinate nature of growth.

Physics-Based State of Health Prediction of Lithium-Ion Battery during Fast Charging

Electrification of the transportation sector and increased use in consumer electronics have driven the increasing demand for lithium-ion batteries (LiBs) (1). Despite their high energy density and long service life, LiBs suffer from capacity degradation due to continuous growth of solid electrolyte interface (SEI) layer and plating of lithium on the anode surface. Graphite, the anode in most LiBs, has a high tendency to catalyze the degradation of the electrolyte consisting of LiPF6 and ethylene carbonate to form an SEI of Li-rich carbonate, phosphate, and fluoride compounds (2, 3). The SEI film grows during service due to the deposition of reaction products and repeated cycles of damage and reformation due to the contraction and expansion associated with volume changes during Li-ion intercalation and deintercalation. Additionally, fast or low-temperature charging of batteries results in lithium plating on the anode surface because the elevated concentration of Li+ on the anode surface results in graphite potential falling below 0V vs. Li+/Li and increased likelihood of Li deposition compared to intercalation (4). Lithium loss due to the side reactions of SEI growth and plating contributes to capacity loss and may increase the likelihood of battery failure. Hence, accurate modeling of the side reactions is required to determine the state of health (SOH) and predict the remaining capacity of LiBs during operation (5).We report an experimentally validated single particle model (SPM) to estimate the influence of SEI growth and Li plating on the capacity changes in Lithium Cobalt Oxide (LCO)/Carbon cells during repeated cycling (6-8). The SPM model idealizes each electrode as a single particle to approximate the cell response. A. Sarkar et al. (5) included the influence of SEI growth, plating, SEI fracture, and temperature in the SPM model to determine the influence of the side reactions on battery performance. The parameters corresponding to side reactions, such as the SEI film growth rate, conductivity of the SEI film, and reversibility of the plating reaction, were determined through comparison of numerical predictions of cell voltage and capacity change with experimental response measured at charging rates of 0.1C and fast charging rate of 2C on PowerStream 35 mAh LCO/C coin cells (Lir2032) as shown in Figure 1. In addition, the coin cells were subjected to charge/discharge experiments at charging rates varying from 0.1C – 5C for 100 cycles. Experimental measurements of the cell capacity changes were compared to model predictions for the different charging rates to validate the modeling assumptions and determine the efficacy of the estimated parameters in describing the cell degradation. The agreement between the model prediction and measured experimental response showed that the single particle model augmented with side reaction mechanisms can describe the cell degradation and is suitable for predicting the remaining capacity and safety of LiBs subjected to a range of charging rates. The model can also predict the accumulation of irreversibly plated lithium on the anode surface during repeated fast charging. The amount of plated lithium determines the severity of dendritic growth, and thus, model predictions of lithium accumulation may be used to estimate the likelihood of battery failure under fast charging conditions. Acknowledgment:This work was supported by the National Science Foundation, Iowa State University, and University of Connecticut.

(Invited) Lifetime Predictive Model of Capacity Loss, Resistance Increase, and Irreversible Thickness Growth

We present a battery lifetime model that predicts Irreversible battery thickness change under constant pressure operation as the battery ages, along with capacity loss and resistance growth. These metrics are very important for predicting lithium-ion battery state of health (SOH) and remaining useful life due to their interdependence with battery packaging and safety. To design and operate battery storage systems safely, we must be able to predict and detect changes in all three SOH metrics over life accurately and simultaneously. Traditionally, these three SOH metrics have been modeled separately. However, we developed a single model that simultaneously predicts battery capacity, resistance, and expansion over its lifetime.In this work, battery degradation is modeled using the single particle model (SPM) framework, including mechanical damage in the electrodes, which results in loss of active material (LAM), and the side reactions for SEI growth and Li plating, which result in loss of lithium inventory (LLI). We introduce an equivalent stress and concentration dependence of stress to the mechanical damage model. Commonly used fatigue models assume symmetric cycles (zero-mean stress) [1]. To account for cycling conditions with different currents on charge and discharge, an equivalent stress that adjusts for non-zero mean stress is needed. The concentration dependency of strain and the resulting stress allows us to capture different degradation rates for cells cycled at different depths of discharge (DOD). Lithium plating at the separator interface is often described as a spatially non-uniform process using the pseudo-2D (P2D) model. This phenomenon can be captured in the SPM framework using a current-dependent dynamic term to account for spatial-nonuniformity of electrolyte dynamics at higher currents.Experimental data from cells cycling with periodic reference performance tests were used to tune the degradation model. In addition to the standard I, V, and T measurements, continuous measurements of the thickness change of the battery pouch cells were recorded. From this data, we extracted the capacity, electrode state of health (eSOH), resistance, and reversible and irreversible expansion. The test conditions were designed to excite different dominant degradation mechanisms (e.g. mechanical damage) by cycling the cells at different conditions (C-rate, temperature, preload pressure, and DOD). The tuning, which uses accelerated aging simulations [2] (to speed up the tuning process), results in a single set of parameters that predicts capacity loss, resistance growth, and irreversible thickness change as the battery ages, even for conditions that were not used for parameter tuning.The tuning is performed in two sequential steps. First, the parameters related to the electrochemical and mechanical degradation rates, which result in LLI and LAM, are tuned to match the extracted eSOH variables at each Reference Performance Test (RPT). The first tuning gives us the amount of plated Li, SEI growth, and mechanical damage in the particles. We then relate these quantities to irreversible expansion using a linear relationship in the case of SEI and mechanical damage and quadratic in the case of Li plating [3]. The same relationship is used for all cells, and this represents the 2nd tuning step. Our data set and calibration are unique in that the dominant degradation mode is the loss of lithium inventory due to the loss of active anode material. Most prior work on lifetime predictive models relied on SEI growth as the dominant degradation mode. Figure 2 shows the tuned model prediction of the three performance metrics over the cycle life of cells for various cycling conditions. The markers represent the measurement at each reference performance test, and the lines correspond to the model.

Diagnosing NMC Battery Aging Modes Using Digital Twin

Traditional lithium-ion battery (LiB) modeling does not provide sufficient information to accurately verify battery performance under real-time dynamic operating conditions, particularly when considering various aging modes and mechanisms. This paper proposes a lithium-ion battery digital twin that can capture real-time data and integrate the strong coupling between SEI layer growth, anode crack propagation, drying up of Electrolytes, and lithium plating. It can be utilized to predict the degradation behavior, voltage-current profiles in dynamic aging conditions, and analyze the lithium inventory loss (LLI) of Nickel-Manganese-Cobalt-Oxide (NMC) lithium-ion batteries.Commercially available 18650 cylindrical NMC Samsung battery cells were investigated. The cathode and anode materials are LiNi0.5Co0.2Mn0.3O2 and synthetic graphite, respectively. Four dynamic aging test cases using 1C, 1.3C, MC (multistep charging), and 2C, were designed and performed at 25 °C. The reference performance test (RPT) was repeated every 100 full equivalent cycles (FECs) until the cells reached 20 % capacity fade. Figure 1 shows the real-time voltage and current profile captured and predicted by the digital twin.The model takes into account LLI induced by SEI growth and lithium plating, aligning with the LLI calibrated from the differential voltage (DV) endpoint shift (Figure 1h). Based on the model results, SEI growth is found to be the primary contributor to capacity loss before 500 FECs. SEI-induced degradation is minimal under the MC protocol, with the capacity loss varying by less than 5.22% across four test cases (Figure 1e). After 500 FECs, anode cracking becomes a non-linear accelerated aging factor. The crack propagation stabilizes in the initial 200 FECs, followed by unstable accelerated growth leading to capacity loss. Subsequently, a rapid acceleration in capacity loss occurs after 700 FECs (Figure 1f). The growth of anode cracks under the MC aging protocol has a much slower effect on capacity loss compared to the 2C and 1.3C before 500 FECs, as strongly confirmed by the post-mortem analysis. In addition, the lithium plating phenomenon triggers two orders of magnitude less capacity loss than SEI growth and cracking at 25 °C. The MC protocol demonstrates an effective reduction in lithium plating capacity loss compared to the other three traditional charging protocols (Figure 1g). This digital twin can represent a firm physical foundation for future physics-informed machine learning development to predict LiBs degradation behavior.Figure 1. Real-time voltage and current captured and predicted by our designed digital twin under (a) 1C-WLTC, (b)1.3C-WLTC, (c) MC-WLTC, and (d) 2C-WLTC aging profiles. Additionally, (f) illustrates capacity loss density for the four protocols attributed to (e) SEI film growth, (f) anode crack propagation, (g) Li plating, and (h) LLI prediction by the digital twin and DV measurement. Figure 1

Prevention of chemotherapy-related bone loss with doxorubicin-loaded solid lipid nanoparticles.

Aim: Breast cancer and its metastases involve high mortality even with advances in chemotherapy. Solid lipid nanoparticles provide a platform for drug delivery, reducing side effects and treatment-induced bone loss. A solid nanoparticle containing doxorubicin was evaluated for its ability to prevent bone loss in a pre-clinical breast cancer model.Methods: We investigated the effects of SLNDox in an aggressive metastatic stage IV breast cancer model, which has some important features that are interesting for bone loss investigation. This study evaluates bone loss prevention potential from solid lipid nanoparticles containing doxorubicin breast cancer treatment, an evaluation of the attenuation of morphological changes in bone tissue caused by the treatment and the disease and an assessment of bone loss imaging using computed tomography and electron microscopy.Results: Chemotherapy-induced bone loss was also observed in tumor-free animals; a solid lipid nanoparticle containing doxorubicin prevented damage to the growth plate and to compact and cancellous bones in the femur of tumor-bearing and healthy animals.Conclusion: The association of solid lipid nanoparticles with chemotherapeutic drugs with proven efficacy promotes the prevention of serious consequences of chemotherapy, reducing tumor progression, increasing quality of life and improving prognosis and survival.

Apolipoprotein E is a novel marker for chondrocytes in the growth plate resting zone.

The resting zone (RZ) in mammalian growth plates is critical for maintaining and regulating chondrocyte turnover during longitudinal bone growth as a control tower and stem cell reservoir. Although recent lineage tracing studies have identified several markers for stem cells in the RZ, these markers only partially label chondrocytes in the RZ, suggesting that the resting chondrocytes (RCs) are a heterogeneous population with different types of stem cells. Since a comprehensive marker for RCs is still lacking, the RZ is generally determined based on ambiguous histological criteria, such as small and round chondrocytes without columnar formation, which may lead to inconsistencies among researchers. Therefore, in this study, we used single-cell RNA sequencing (scRNAseq) of growth plate chondrocytes followed by validation by fluorescence in situ hybridization (FISH) to precisely annotate cell clusters in scRNAseq and search for a marker of RCs. The scRNAseq analysis revealed that apolipoprotein E (Apoe) was the top-hit gene, which was ubiquitously expressed in the RC cluster. FISH confirmed that Apoe was exclusively localized to the histologically defined RZ. In newly generated Apoe-mCherry knock-in mice, we further confirmed that mCherry expression mirrored the distribution of Apoe-expressing chondrocytes in the RZ particularly after the formation of the secondary ossification center. These mCherry+ RCs were slow cycling in vivo and exhibited stem cell properties both in vitro and in vivo. Moreover, APOE was detected in human growth plate RCs. These findings suggest that Apoe is a novel pan-RC marker in both mouse and human growth plates.

Tartrate-resistant acid phosphatase (TRAP/ACP5) promotes bone length, regulates cortical and trabecular bone mass, and maintains growth plate architecture and width in a sex- and site-specific manner in mice

Tartrate-resistant acid phosphatase (TRAP) serum levels reflect osteoclast number, bone remodeling activity, and fracture risk. Deletion or loss of function of TRAP results in short stature in mice and man. Yet, the impact and mechanisms of TRAP for the site- and sex-specific development of bone and cartilage is not well understood. Here, we use a global TRAP knockout (TRAPKO) and wildtype littermate control (WT) mice of both sexes to investigate TRAP as a possible sex- and site-specific regulator of bone and growth plate development. TRAPKO mice of both sexes weighed less and had shorter tibial length than their WT, features that were more accentuated in male than female TRAPKO mice. These changes were not associated with a general reduction in growth as not all organs displayed a proportionally lower mass, and serum IGF-1 was unchanged. Using μCT and site-specificity analysis of the cortical bone revealed wider proximal tibia, a higher trabecular thickness, and lower trabecular separation in male TRAPKO compared to WT mice, an effect not seen in female mice. Histomorphometric analysis revealed that the growth plate height as well as height of terminal hypertrophic chondrocytes were markedly increased, and the number of columns was decreased in TRAPKO mice of both sexes. These effects were more accentuated in female mice. Proliferation and differentiation of bone marrow derived macrophages into osteoclasts, as well as C-terminal cross links were normal in TRAPKO mice of both sexes. Collectively, our results show that TRAP regulates bone and cartilage development in a sex-and site-specific manner in mice.

Tibial Damage Caused by T-2 Toxin in Goslings: Bone Dysplasia, Poor Bone Quality, Hindered Chondrocyte Differentiation, and Imbalanced Bone Metabolism.

T-2 toxin, the most toxic type A trichothecene, is widely present in grain and animal feed, causing growth retardation and tissue damage in poultry. Geese are more sensitive to T-2 toxin than chickens and ducks. Although T-2 toxin has been reported to cause tibial growth plate (TGP) chondrodysplasia in chickens, tibial damage caused by T-2 toxin in geese has not been fully demonstrated. This study aims to investigate the adverse effects of T-2 toxin on tibial bone development, bone quality, chondrocyte differentiation, and bone metabolism. Here, forty-eight one-day-old male Yangzhou goslings were randomly divided into four groups and daily gavaged with T-2 toxin at concentrations of 0, 0.5, 1.0, and 2.0 mg/kg body weight for 21 days, respectively. The development of gosling body weight and size was determined by weighing and taking body measurements after exposure to different concentrations of T-2 toxin. Changes in tibial development and bone characteristics were determined by radiographic examination, phenotypic measurements, and bone quality and composition analyses. Chondrocyte differentiation in TGP and bone metabolism was characterized by cell morphology, tissue gene-specific expression, and serum marker levels. Results showed that T-2 toxin treatment resulted in a lower weight, volume, length, middle width, and middle circumference of the tibia in a dose-dependent manner (p < 0.05). Moreover, decreased bone-breaking strength, bone mineral density, and contents of ash, Ca, and P in the tibia were observed in T-2 toxin-challenged goslings (p < 0.05). In addition, T-2 toxin not only reduced TGP height (p < 0.05) but also induced TGP chondrocytes to be disorganized with reduced numbers and indistinct borders. As expected, the apoptosis-related genes (CASP9 and CASP3) were significantly up-regulated in chondrocytes challenged by T-2 toxin with a dose dependence, while cell differentiation and maturation-related genes (BMP6, BMP7, SOX9, and RUNX2) were down-regulated (p < 0.05). Considering bone metabolism, T-2 toxin dose-dependently and significantly induced a decreased number of osteoblasts and an increased number of osteoclasts in the tibia, with inhibited patterns of osteogenesis-related genes and enzymes and increased patterns of osteoclast-related genes and enzymes (p < 0.05). Similarly, the serum Ca and P concentrations and parathyroid hormone, calcitonin, and 1, 25-dihydroxycholecalciferol levels decreased under T-2 toxin exposure (p < 0.05). In summary, 2.0 mg/kg T-2 toxin significantly inhibited tibia weight, length, width, and circumference, as well as decreased bone-breaking strength, density, and composition (ash, calcium, and phosphorus) in 21-day-old goslings compared to the control and lower dose groups. Chondrocyte differentiation in TGP was delayed by 2.0 mg/kg T-2 toxin owing to cell apoptosis. In addition, 2.0 mg/kg T-2 toxin promoted bone resorption and inhibited osteogenesis in cellular morphology, gene expression, and hormonal modulation patterns. Thus, T-2 toxin significantly inhibited tibial growth and development with a dose dependence, accompanied by decreased bone geometry parameters and properties, hindered chondrocyte differentiation, and imbalanced bone metabolism.

Metabolically healthy obesity in adults with X-linked hypophosphatemia.

X-linked hypophosphatemia (XLH) is characterized by increased concentrations of circulating fibroblast growth factor 23 (FGF-23) resulting in phosphate wasting, hypophosphatemia, atypical growth plate and bone matrix mineralization. Epidemiologic studies suggest a relationship between FGF-23, obesity, and metabolic dysfunction. The prevalence of overweight and obesity is high in children with XLH. We aimed to evaluate the prevalence of obesity and metabolic complications in adults with XLH. We conducted a prospective cohort study in adult XLH patients from a single tertiary referral center. The proportion of patients with a BMI >25 kg/m2 was the main outcome measure. Body fat mass percentage (FM%) and adipose tissue surfaces were secondary outcome measures. Glucose homeostasis (plasma glucose and insulin concentrations after fasting and 2 hours after an oral glucose tolerance test) was explored in a subgroup of patients and compared with age-, sex-, and BMI-matched healthy controls. Among 113 evaluated patients, 85 (75%) were female and 110 (97%) carried a PHEX mutation. Sixty-three (56%) patients were overweight or obese, with a median BMI of 25.3 [IQR, 22.7; 29.2] kg/m2. BMI was correlated with FM%, abdominal and thigh subcutaneous and intra-abdominal adipose tissue surfaces. The prevalence of impaired fasting glucose, impaired glucose tolerance, and diabetes was not different between XLH patients and matched controls. The prevalence of overweight and obesity is high among XLH patients and is associated with excess fat mass. However, the prevalence of glucose homeostasis abnormalities is not increased in patients compared to healthy controls, suggesting that metabolically healthy overweight or obesity predominates.

MRI T1-Weighted Fat Segmentation Based on Active Contour for Osteosarcoma Patients

Osteosarcoma (OS) is the most common and frequent primary bone cancer in children and adolescents. This type of bone cancer often developed at the long bones’ extremities close to the metaphyseal growth plates. To address these issues, OS quantitative analysis is performed using Magnetic Resonance Imaging (MRI) to plan surgical procedures and track the effectiveness of treatment. Fat suppression is commonly employed to eliminate the fat signal from T1-Weighted MRI sequence. The suppressed fat signal in T1-Weighted is important and often used to identify abnormalities in other MRI sequences. In clinical, MRI images must be interpreted by a radiologist. Manually outlining the tumour location is laborious and subjective. Image processing involves segmentation to separate information from the desired target region of the image. Active Contour (AC) is an algorithm often used in medical images for segmentation. Nevertheless, the process of mask initialization can be challenging and requires careful attention. This study proposes a method to define the mask initialization so that the AC has a starting point to extract fat in T1-Weighted for the purpose of fat suppression. From the results obtained, AC with the proposed mask initialization method successfully segmented the fat in T1-Weighted MRI images with accuracy, precision, recall and F1-score of 0.92, 0.86, 0.88 and 0.89 respectively.

The Association Between the Development of Cam Morphology During Skeletal Growth in High-Impact Athletes and the Presence of Cartilage Loss and Labral Damage in Adulthood: A Prospective Cohort Study With a 12-Year Follow-up

Background: Cam morphology develops during skeletal growth, but its influence on cartilage and the labrum in high-impact athletes later in life is unknown. Purpose: To (1) explore the association between the presence and duration of cam morphology during adolescence and the cartilage and labral status 7 to 12 years later and (2) report the prevalence of cartilage loss and labral damage in a population of young male athletes (<32 years old) who played professional soccer during skeletal growth. Study Design: Cohort study (Prognosis); Level of evidence, 2. Methods: A total of 89 healthy male academy soccer players from the Dutch soccer club Feyenoord (aged 12-19 years) were included at baseline. At baseline and 2.5- and 5-year follow-ups, standardized supine anteroposterior pelvis and frog-leg lateral radiographs of each hip were obtained. At 12-year follow-up, magnetic resonance imaging of both hips was performed. Cam morphology was defined by a validated alpha angle ≥60° on radiographs at baseline or 2.5- or 5-year follow-up when the growth plates were closed. Hips with the presence of cam morphology at baseline or at 2.5-year follow-up were classified as having a “longer duration” of cam morphology. Hips with cam morphology only present since 5-year follow-up were classified as having a “shorter duration” of cam morphology. At 12-year follow-up, cartilage loss and labral abnormalities were assessed semiquantitatively. Associations were estimated using logistic regression, adjusted for age and body mass index. Results: Overall, 35 patients (70 hips) with a mean age of 28.0 ± 2.0 years and mean body mass index of 24.1 ± 1.8 participated at 12-year follow-up. Cam morphology was present in 56 of 70 hips (80%). The prevalence of cartilage loss was 52% in hips with cam morphology and 21% in hips without cam morphology (adjusted odds ratio, 4.52 [95% CI, 1.16-17.61]; P = .03). A labral abnormality was present in 77% of hips with cam morphology and in 64% of hips without cam morphology (adjusted odds ratio, 1.99 [95% CI, 0.59-6.73]; P = .27). The duration of cam morphology did not influence these associations. Conclusion: The development of cam morphology during skeletal growth was associated with future magnetic resonance imaging findings consistent with cartilage loss in young adults but not with labral abnormalities.

Intermittent mechanical loading on mouse tibia accelerates longitudinal bone growth by inducing PTHrP expression in the female tibial growth plate.

It is not clear as to whether weight bearing and ambulation may affect bone growth. Our goal was to study the role of mechanical loading (one of the components of ambulation) on endochondral ossification and longitudinal bone growth. Thus, we applied cyclical, biologically relevant strains for a prolonged time period (4 weeks) to one tibia of juvenile mice, while using the contralateral one as an internal control. By the end of the 4-week loading period, the mean tibial growth of the loaded tibiae was significantly greater than that of the unloaded tibiae. The mean height and the mean area of the loaded tibial growth plates were greater than those of the unloaded tibiae. In addition, in female mice we found a greater expression of PTHrP in the loaded tibial growth plates than in the unloaded ones. Lastly, microCT analysis revealed no difference between loaded and unloaded tibiae with respect to the fraction of bone volume relative to the total volume of the region of interest or the tibial trabecular bone volume. Thus, our findings suggest that intermittent compressive forces applied on tibiae at mild-moderate strain magnitude induce a significant and persistent longitudinal bone growth. PTHrP expressed in the growth plate appears to be one growth factor responsible for stimulating endochondral ossification and bone growth in female mice.