Search Results (282)

Background/Objectives: Neurogenic heterotopic ossification (HO) is an abnormal formation of lamellar bone in soft tissues, frequently developing near major joints in patients with spinal cord injury. While imaging provides valuable diagnostic insights, large and anatomically complex HO often requires advanced preoperative planning to minimize surgical risks. This study presents the development and clinical application of a structured six-stage workflow integrating three-dimensional (3D) technologies for the preoperative planning and surgical resection of giant iliofemoral HO. Materials and Methods: A workflow was developed comprising: (1) 3D imaging acquisition, (2) creation of a virtual model, (3) production of a life-size physical model, (4) preoperative simulation, (5) surgical resection, and (6) postoperative imaging validation. The workflow was applied to a 50-year-old male with paraplegia after a T12 fracture who developed a 26 cm iliofemoral bony bridge, confirmed by computed tomography and 3D reconstruction. Results: The physical model provided a precise anatomical reference, enabling detailed surgical rehearsal and safe planning of neurovascular dissection. Resection was performed using combined orthopedic and vascular techniques. The hip joint was preserved, and postoperative rehabilitation achieved improved range of motion and patient handling without major complications. Conclusions: This structured 3D-assisted workflow enhanced anatomical understanding and surgical precision in this complex case. The framework is applicable to other extensive ossifications with intricate anatomical relationships and warrants further evaluation in larger series. Full article

Prenatal exposure to aflatoxin B₁ (AFB₁) poses a significant risk to fetal development and is associated with reduced birth weight in humans. Experimental studies consistently show that AFB₁ induces fetal abnormalities, with skeletal malformations and ossification defects being the most common. However, the specific impact of AFB₁ on fetal osteogenesis remains unclear. Given this knowledge gap, this study aimed to review the existing literature concerning the pathogenesis of AFB₁ and its potential influence on bone development. The primary mechanisms implicated in AFB₁’s impact on bone include dysfunction in vitamin D and calcium metabolism, alterations in parathyroid hormone production and function, induction of inflammatory responses, and oxidative stress. Collectively, these mechanisms have the potential to impair osteoblast and osteoclast function and, consequently, compromise ossification. Based on these findings, studies should explore and elucidate the effects of AFB₁. Elucidating these mechanisms is crucial for mitigating the deleterious impacts of AFB₁ on fetal skeletal development. Full article

Background/Objectives: Cochlear implants (CIs) constitute a viable method for auditory rehabilitation in patients with profound sensorineural hearing loss after temporal bone fractures (TBFs). These patients comprise a challenging population due to the anatomical deformity and neural injury. Methods: By performing this systematic review, we attempted to evaluate the viability of CIs in the context of TBF. The literature search, across Pubmed/MEDLINE, Scopus and Google Scholar, was performed under the PRISMA guidelines. The selected time period was from December 1995 to September 2025. The final analysis included 11 manuscripts. The majority of the studies were retrospective case series with a moderate risk of bias. Results: The primary outcome was postoperative auditory function, evaluated with speech perception tasks and aided sound-field pure-tone audiometry. The secondary outcomes were the report of radiological and electrophysiologic prognosticators of implants’ viability, timing of surgery, procedural feasibility and complications. Across the studies, CIs conferred meaningful auditory benefit when the cochlear nerve was intact. High-Resolution Computed Tomography (CT) was utilized for TBF classification and cochlear patency, whereas Magnetic Resonance Imaging (MRI) and a promontory test were crucial for the assessment of neural integrity. Prompt placement, optimally within 12 months after trauma, was related to improved outcomes by limiting cochlear fibrosis and ossification. Despite patients’ impedance fluctuation, restricted speech perception in noise and frequent abnormal facial nerve excitation, the overall audiologic and speech discrimination results are comparable to non-trauma recipients. Conclusions: A CI appears to be the choice of treatment over auditory brainstem implants, as long as the cochlear nerve remains intact. Rapid implantation in well-selected patients coupled with ordinal mapping and follow-up can restore dysfunctional hearing and improve patients’ quality of life. Full article

Background: Delayed or non-union fractures comprise 5–10% of cases, indicating the need for biologic interventions. Recombinant human bone morphogenetic protein-2 (rhBMP-2) is a potent osteoinductive agent; yet, collagen carrier-based uncontrolled release causes adverse events. We evaluated the safety and efficacy of a hydroxyapatite (HA) carrier-based rhBMP-2 delivery system for acute traumatic upper and lower fractures exhibiting bone defects. Methods: This prospective, multicenter, single-arm clinical trial enrolled 90 patients who underwent surgery using a hydroxyapatite (HA) carrier-based rhBMP-2 delivery system (Novosis^TM). Radiographically validated union at 6 and 12 months post-surgery and treatment success (union without additional surgery) were used to assess efficacy. The incidence, type, and severity of all device-related adverse events during follow-up were monitored by investigators to evaluate safety. Results: Of the 90 patients enrolled, 81 were included in the full analysis set. The mean age was 58.5 years, and 18.6% (15/81) had open fractures. At 6 months post-surgery, radiographically validated union was achieved in 81.5% (66/81) of patients, increasing to 96.2% (77/81) at 12 months after surgery. Treatment success was 95.0% (76/81). Adverse events were rare (1/81, 1.2%). No ectopic ossification, systemic complications, or severe inflammatory responses were observed. Conclusions: HA-based rhBMP-2 intervention demonstrated favorable union rates and safety with minimal complications in acute upper and lower fractures with bone defects. The biocompatibility and controlled-release properties of HA likely improved efficacy and reduced complications. Results should be interpreted as feasibility data from a heterogeneous case series without a control group. Larger randomized controlled comparative trials are warranted for optimal dosing and evaluating efficacy and cost-effectiveness. Full article

Background/Objectives: Diseases affecting the craniofacial skeleton are normally associated with disturbances in the regulation of cellular differentiation, the development of bone structures, and changes in bone density and ossification. Thus, the objective of this integrative review is to evaluate the published scientific literature from the last 8 years concerning the impact of genetics on some craniofacial dysplasias. Our aim covers the identification of oral cavity alterations to those dysplasias, through the most common orofacial manifestations. Three dysplasias were selected to be part of this integrative review: cleidocranial dysplasia, ectodermal dysplasia and Apert syndrome. Methods: For this purpose, a bibliographic search was performed in the PubMed, ScienceDirect, Web of Science and Google Scholar databases with several keywords combined with each other. The research question of this review was as follows: “What is the impact of genetic factors on the development of craniofacial dysplasias and associated oral malformations?”. Results: After selecting the articles through the application of inclusion and exclusion criteria, 11 articles were selected for this review. Conclusions: Genetics plays a crucial role in craniofacial dysplasias and subsequent oral malformations. The main conclusion was that mutations in different genes can lead to identical phenotypes, while mutations in the same gene can present slight phenotypic differences depending on where they occur. In the future, it would be important to conduct studies with larger samples and control groups that include genetic testing to allow for a more comprehensive study on the impact of genetics on craniofacial dysplasias. Full article

Long bone formation in vertebrates proceeds via endochondral ossification, a sequential process that begins with mesenchymal condensation, advances through cartilage anlage formation, and culminates in its replacement by mineralized bone. Recent advances in inducible lineage tracing and single-cell genomics have revealed that, rather than being a uniform event, mesenchymal condensation rapidly segregates into progenitor pools with distinct fates. Centrally located Sox9⁺/Fgfr3⁺ chondroprogenitors expand into the growth plate and metaphyseal stroma, peripheral Hes1⁺ boundary cells refine condensation via asymmetric division, and outer-layer Dlx5⁺ perichondrial cells generate the bone collar and cortical bone. Concurrently, dorsoventral polarity established by Wnt7a–Lmx1b and En1 ensures that dorsal progenitors retain positional identity throughout development. These lineage divergences integrate with signaling networks, including the Ihh–PTHrP, FGF, BMPs, and WNT/β-catenin networks, which impose temporal control over chondrocyte proliferation, hypertrophy, and vascular invasion. Perturbations in these programs, exemplified by mutations in Fgfr3, Sox9, and Dlx5, underlie region-specific skeletal dysplasias, such as achondroplasia, campomelic dysplasia, and split-hand/foot malformation, demonstrating the lasting impacts of embryonic patterning errors. Based on these insights, regenerative strategies are increasingly drawing upon developmental principles, with organoid cultures recapitulating ossification centers, biomimetic hydrogels engineered for spatiotemporal morphogen delivery, and stem cell- or exosome-based therapies harnessing developmental microRNA networks. By bridging developmental biology with biomaterials science, these approaches provide both a roadmap to unravel skeletal disorders and a blueprint for next-generation therapies to reconstruct functional bones with the precision of the embryonic blueprint. Full article

Medication-related osteonecrosis of the jaw (MRONJ) is a devastating complication arising primarily after invasive dentoalveolar procedures in patients treated with antiresorptive, antiangiogenic, or targeted therapies. Although recognized risk factors are established, the distinctive vulnerability of jawbones compared to long bones is not fully understood. This review comprehensively synthesizes recent advances regarding the embryological, anatomical, and physiological disparities that contribute to region-specific susceptibility to MRONJ. Recent evidence suggests that jawbones diverge significantly from long bones in embryonic origin, ossification pathways, vascular architecture, innervation patterns, and regenerative capacities. These differences affect bone metabolism, healing dynamics, response to pharmacologic agents, and local cellular activities, such as enhanced bisphosphonate uptake and specialized microcirculation. Experimental and clinical evidence reveals that mandibular periosteal cells exhibit superior osteogenic and angiogenic potentials, and the jaws respond differently to metabolic challenges, trauma, and medication-induced insults. Furthermore, site-specific pharmacologic and inflammatory interactions, including altered periosteal microcirculation and leukocyte–endothelial interactions, may explain the development of MRONJ, although rare cases of medication-related osteonecrosis have also been reported in long bones. Emerging research demonstrates that immune dysregulation, particularly M1 macrophage polarization with overexpression of matrix metalloproteinase-13 (MMP-13), plays a crucial role in early MRONJ development. Understanding these mechanisms highlights the critical need for region-specific preventive measures and therapeutic strategies targeting the unique biology of jawbones. This comparative perspective offers new translational insights for designing targeted interventions, developing tissue engineering solutions, and improving patient outcomes. Future research should focus on gene expression profiling and cellular responses across skeletal regions to further delineate MRONJ pathogenesis and advance personalized therapies for affected patients. Full article

Scheuermann’s kyphosis (SK) is a rigid dorsal kyphosis of unclear pathophysiological origin. The aim of this review is to summarise current theories and both clinical and experimental findings regarding the underlying mechanisms of SK. Emerging evidence highlights the significant role of excessive mechanical loading as a major contributor to defective growth of the cartilaginous vertebral endplate. This is associated with the formation of Schmorl’s nodes, disruption of the ring apophysis, and compromised intervertebral disc integrity—ultimately resulting in vertebral body wedging and thickening of the anterior longitudinal ligament. In addition, numerous studies have investigated the genetic contribution and underlying molecular mechanisms involved in the pathogenesis of SK. Recent in vivo findings suggest an association between asymmetric mechanosensory activation of cerebrospinal fluid (CSF), contacting neurons, and defective Reissner fibre signalling, which may contribute to abnormal spinal morphogenesis in the sagittal thoracic plane. These findings indicate a potential link between altered CSF dynamics and the development of SK. Taken together, the evidence supports a multifactorial aetiology, with both genetic and biomechanical factors playing central roles in the development of Scheuermann’s kyphosis. The interpretation of the underlying pathophysiological mechanism could result in the early detection of the subjects that may have genetical predisposition for SK appearance and the development of target molecular treatments in order to counter the progression of the deformity. Full article

Background/Objectives: Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic bone disorder, leading to progressive immobilization through the formation of bone in muscles, tendons, and ligaments. A variant in the ACVR1 gene results in a constitutively overactive ALK2 receptor, leading to the aberrant activation of the SMAD1/5/9 pathway. This activation occurs not only in response to Activin A, which does not normally activate this pathway, but also through heightened sensitivity to BMP ligands and even in the absence of ligand binding. This dysregulated signaling ultimately drives the formation of heterotopic ossification. The inhibition of the altered ALK2 receptor holds promise as a potential treatment strategy that is currently being investigated in several trials. In this study, we performed an in vitro characterization of novel kinase inhibitor KTI-2338 with high selectivity for the ALK2 receptor. Methods: Dermal human FOP and control fibroblasts were cultured in osteogenic medium with and without the inhibitor to assess the effect on transdifferentiation into osteoblast-like cells. Results: Compound KTI-2338 elicited effects consistent with inhibiting aberrant Activin A signaling and receptor sensitization, through reductions in osteogenic markers and pSMAD1/5/9 expression levels. In line with this, a pattern of reduced Alizarin Red staining was observed following treatment with the compound, indicating reduced mineralization. Conclusions: These findings indicate that kinase inhibitor KTI-2338 disrupts the pathological processes underlying FOP and may offer a new therapeutic option for this devastating disease. Full article

Estimating bone age is essential for accurate diagnoses, appropriate care based on biological age, and fairness in legal matters. In the Indian medicolegal context, determining age through a clinical approach involves analyzing multiple joints; however, the traditional method can be tedious and subjective, relying heavily on human expertise, which may lead to biased decisions in age-related legal disputes. Moreover, commonly used radiographs often exhibit pixel-level variations due to heterogeneous contrast, which complicate segmentation tasks and lead to inconsistencies and reduced model performance. The study presents a multifocal region-based symbolic segmentation technique to automatically retain the soft-tissue region that harbors a growth pattern of an ossification center. Experimental results demonstrate an 84.5% Jaccard similarity, an 81.4% Dice coefficient, an 88.3% precision, a 90.0% recall, and a 91.5% pixel accuracy on a novel multifocal dataset of Indian inhabitants. The proposed segmentation technique outperforms U-Net, Attention U-Net, TransU-Net, DeepLabV3+, Adaptive Otsu, and Watershed segmentation in terms of accuracy, indicating strong generalizability across joints and improving reliability. Compared with 86.4% without segmentation, the proposed integration of segmentation with VGG16 classification increases the overall accuracy to 93.8%, demonstrating that target-focused-region processing reduces unnecessary computations and improves feature discrimination without sacrificing accuracy. Full article

The present study aimed to assess the potential maternal toxicity of Ficus deltoidea var. kunstleri aqueous extract in pregnant rats, along with its impact on maternal hepatic drug metabolism and foetal skeletal development. Pregnant rats were divided into five groups and orally administered varying doses of F. deltoidea aqueous extract (0, 250, 500, 1000, and 2000 mg/kg body weight) from gestation day 6 to 20. Throughout the administration period, clinical observations, body weight, and food and water intake were monitored. On gestation day 21, the pregnant rats were sacrificed, and their vital organs and foetuses were collected for analysis. Gene expression related to hepatic drug metabolism was evaluated using the RT2 Profiler™ PCR array. Foetal external morphology was examined for abnormalities, and skeletal structures were stained with Alizarin Red to assess the effects of F. deltoidea aqueous extract on bone ossification during organogenesis. No maternal toxicity was observed, except for a significant increase in liver weight in the treated groups (p < 0.05). Analysis of 84 genes revealed significant changes in 15, 4, and 11 genes in the 250, 500, and 2000 mg/kg body weight groups, respectively. Notably, Gpx5 and Pkm, both phase II metabolising enzyme genes were downregulated in a dose-dependent manner. Despite some skeletal variations, the extract did not induce foetal external malformations or skeletal abnormalities. The significant increase in maternal liver weight, together with the downregulation of Gpx5 and Pkm, suggests an adaptive hepatic response to the extract rather than an adverse effect. These findings also suggest that F. deltoidea var. kunstleri aqueous extract does not cause embryo toxicity, foetal growth retardation, or developmental malformations, particularly in skeletal formation. The developmental no-observed-adverse-effect level (NOAEL) was determined to be >2000 mg/kg/day via oral administration. Further research is warranted to explore the synergistic interactions of genes involved in hepatic drug metabolism in response to the extract. Full article

The development of intermuscular bones (IBs) in teleost fish is regulated by osteogenic genes, but the upstream signals that initiate ossification remain elusive. Given the spatiotemporal correlation between IB formation and swimming behavior, mechanical stimuli from muscle activity have been hypothesized as potential regulators. In this study, we investigated the role of the muscle-specific microRNA miR499 in this process. Using CRISPR/Cas9-generated miR499 knockout zebrafish, we demonstrated that the mutant of miR499 induces a fast-twitch muscle phenotype through the upregulation of sox6, accompanied by increased fast-myosin gene expression and fast-twitch fiber proliferation. This shift led to distinct locomotor alterations, characterized by reduced tail-beat frequency and increased stride length. Crucially, these changes resulted in delayed IB ossification onset, slower ossification rates, and simplified morphology. The total ossification area decreased by 27%. Molecular analysis revealed a downregulation of osteogenic genes in IB tissue. Our findings establish miR499 as a key regulator of a muscle–bone functional axis, where miRNA-mediated muscle fiber specification determines mechanical output that subsequently guides IB development. This work provides new insights into the mechanobiological regulation of skeletal development and identifies a promising genetic target for aquaculture breeding programs aimed at attenuated IBs. Full article

Background: The styloid process is a slender, cylindrical bony projection of the temporal bone, showing marked interindividual variability in length, orientation, and degree of ossification. Its abnormal elongation, defined as exceeding 30 mm, is often associated with Eagle’s syndrome but may also occur as an incidental anatomical variant. Objective: This study reports two rare cases of abnormally long styloid processes without ossification of the stylohyoid ligament, identified in adult dry skulls from the osteological collection of the “Olga Necrasov” Centre of Anthropological Research, Iași, Romania, and provides morphological and CT-based characterization. Materials and Methods: Both skulls were examined macroscopically and by CT, with 3D reconstructions being used for morphometric analysis. Results: In Case 1, the left SP measured 62 mm, corresponding to Langlais type I elongation, with no evidence of pseudoarticulation or ligamentous ossification. In Case 2, the left SP was elongated to 33 mm and fusiform in shape, while the contralateral (right) SP was completely absent, a highly uncommon anatomical variation scarcely reported in the literature. Both findings were confirmed by CT imaging. Conclusions: The coexistence shows that the stylohyoid complex cand vary greatly during development. Such findings expand the spectrum of known anatomical variants of the stylohyoid complex and underscore the importance of detailed morphologic and imaging evaluation of the styloid region in both anatomical and clinical contexts. Full article

Optimal mechanical parameters for successful bone-healing remain unclear despite their critical influence on fracture outcomes, and the timing of post-surgery mobilization is still controversial despite many clinical observations and pre-clinical studies. In this bioreactor in vitro work, we investigate the effect of fundamental parameters such as timing, duration, and frequency of mechanical stimulation on the endochondral bone-healing paths, specifically on the hypertrophic chondrocyte differentiation of naïve human mesenchymal stromal cells (hMSCs). Human MSCs encapsulated in Gelatin-Methacryloyl hydrogels (GelMa) were subjected to three different 10% strain protocols: P1 (168 long-break cycles spread over 14 days), P2ce (cycle equivalent: 168 short-break cycles condensed in 42-min stimulation followed by 14 days free swelling), and P2te (time equivalent—14 days continuous stimulation, 80′640 short-break cycles). In the free-swelling control group, samples were cultured for 14 days without any mechanical stimulation. Our results confirmed that 10% strain induces a robust hypertrophic chondrocyte differentiation of naïve MSCs in all three tested protocols, as demonstrated by enlarged cell size, rounded morphology, robust upregulation of hypertrophic markers (COL10A1, MMP13, RUNX2, ALP), and reduced glycosaminoglycan production. Of particular interest, we show that P2ce (early short stimulation) was as effective as the two extended stimulation protocols, suggesting that initial mechanical signals are sufficient to trigger cell differentiation toward a hypertrophic chondrocyte phenotype that continues even after stimulation ceases. These in vitro findings provide crucial insights into the cellular basis of endochondral ossification during the early phase of loading and show a beneficial long-term effect of early mechanical stimulation. By demonstrating that the cellular mechanobiology of hypertrophic differentiation responds to brief early stimulation, our findings provide a scientific foundation to guide future in vivo investigations on how rehabilitation protocols could influence fracture healing. Full article

A traumatic elbow dislocation that remains unreduced for more than three weeks is considered a neglected elbow dislocation. We report a case of a patient with a neglected elbow dislocation combined with a terrible triad injury (elbow dislocation with fractures of the coronoid process and radial head). Initially, the patient was managed with three weeks of cast immobilization followed by physiotherapy. However, six months after the trauma, he presented to our clinic with severe heterotopic ossification, significant pain, and nearly complete elbow stiffness. An open surgical intervention was performed, involving excision of the heterotopic bone, reduction in the dislocation, and suturing of the anterior capsule to the coronoid process. Given the irreparable fracture of the radial head, radial head arthroplasty was also performed. At 18-month follow-up, the elbow was stable and pain-free, with flexion–extension of 80°, pronation of 85°, and supination of 80°. This case underscores the critical importance of early diagnosis and intervention to prevent long-term complications in neglected elbow dislocations. Full article