Ectopic Ossification Research Articles

Pathogenesis of thoracic ossification of the ligamentum flavum.

Thoracic ossification of the ligamentum flavum (TOLF) is characterized by ectopic ossification of the ligamentum flavum in the thoracic spine and is considered the main cause of thoracic spinal stenosis and spinal cord disease. Osteoblast specific transcription factor Osterix (Osx) is required for bone formation, and there is no bone formation or ossification without Osx. Surgical intervention is recognized as the only effective method for TOLF treatment with set of complications. However, underlying mechanisms of TOLF are not well understood. This paper summarizes the pathogenesis of TOLF. Some relevant factors have been discussed, such as mechanical stress, genetic susceptibility genes, endocrine and trace element metabolism abnormalities, which may associate with TOLF. More recent studies using proteomics technology and RNA sequencing approach have discovered that some new factors participate in TOLF by upregulation of Osx gene expression including inflammatory factors. TOLF is a unique disease involving multiple factors. On the other hand, studies on TOLF pathogenic mechanism may provide new ideas for finding possible upstream regulatory factors of Osx and further developing novel drugs to stimulate new bone formation to treat osteoporosis.

Effect of Mutation Type on Ectopic Ossification Among Adult Patients With X-Linked Hypophosphatemia.

Causative factors for ectopic ossifications in X-linked hypophosphatemia (XLH) remain to be elucidated. This work aimed to investigate the genotype-phenotype correlations between the phosphate-regulating endopeptidase homologue, X-linked gene (PHEX) and ectopic ossifications in XLH. Biochemical data, spinal computed tomography scans, and x-rays of hip/knee joints were retrospectively reviewed. Genetic analysis and the measurement of plasma inorganic pyrophosphate (PPi)-a potent inhibitor of tissue calcification-were performed. The effect of PHEX mutations on protein function was predicted using nonsense-mediated decay (NMD) and 3-dimensional structure modeling. The index of ossification of the anterior/posterior longitudinal ligament and yellow ligament (OA/OP/OY index) and the sum of the OA/OP/OY index (OS index) were used to quantify the severity of spinal ligament ossification. The severity of the hip/knee osteoarthritis was evaluated by the Kellgren-Lawrence classification. We examined 24 distinct pathogenic PHEX variants in 28 patients from a study population of 33 individuals in 27 unrelated, nonconsanguineous families. Among the 31 patients whose plasma samples were analyzed for PPi, 14 patients (45%) showed decreased plasma PPi concentrations; however, PPi concentrations did not correlate with mutation type or ectopic ossification. Fibroblast growth factor 23 levels in women with NMD-insensitive mutations trended lower than in men with NMD-sensitive mutations but failed to reach statistical significance. Both models revealed no correlations between PHEX pathogenic variant and ectopic ossification. Neither modeling found correlates between PHEX pathogenic variants and ectopic ossification. The effects of PPi on ectopic ossifications in adults with XLH revealed trends that should be investigated with a large sample size.

Transcriptome-Optimized Hydrogel Design of a Stem Cell Niche for Enhanced Tendon Regeneration.

Bioactive hydrogels have emerged as promising artificial niches for enhancing stem cell-mediated tendon repair. However, a substantial knowledge gap remains regarding the optimal combination of niche features for targeted cellular responses, which often leads to lengthy development cycles and uncontrolled healing outcomes. To address this critical gap, an innovative, data-driven materiomics strategy is developed. This approach is based on in-house RNA-seq data that integrates bioinformatics and mathematical modeling, which is a significant departure from traditional trial-and-error methods. It aims to provide both mechanistic insights and quantitative assessments and predictions of the tenogenic effects of adipose-derived stem cells induced by systematically modulated features of a tendon-mimetic hydrogel (TenoGel). The knowledge generated has enabled a rational approach for TenoGel design, addressing key considerations, such as tendon extracellular matrix concentration, uniaxial tensile loading, and in vitro pre-conditioning duration. Remarkably, our optimized TenoGel demonstrated robust tenogenesis in vitro and facilitated tendon regeneration while preventing undesired ectopic ossification in a rat tendon injury model. These findings shed light on the importance of tailoring hydrogel features for efficient tendon repair. They also highlight the tremendous potential of the innovative materiomics strategy as a powerful predictive and assessment tool in biomaterial development for regenerative medicine.

Surgical Treatment of the Frontal Plane Distal Humerus Fractures

The frontal plane fractures of the distal humerus are rare. The small intraarticular fragments, the commonly encountered osteoporosis and the specific anatomy make the successful osteosynthesis a challenge. For a period of 15 years in First Clinic of Orthopaedic Traumatology 27 patients with capitulotrochlear fractures were treated. Of them, 12 women and 3 men were followed. The fractures were classified after Dubberley as follows: Type 1А - 1, type 2А - 2, type 2В - 3, type 3А - 5, type 3В – 1, and type 4В - 3. A plethora of surgical exposures were used - extended lateral, paratricipital, a combination of medial and lateral, dorsal with olecranon osteotomy. Primary TEA was performed in 3 patients: Type 3A - 1, type 3В – 1, and type 4В - 1. The patients were followed for a period of 12 months to 8 years. The results were evaluated by the MEPS, DASH and McGowan scores. The final ROM, compared to the contralateral side, was recorded. The average scores are comparable with the ones in a number of publications in the referent literature. As evaluated by MEPS, excellent results were found in 53% of patients, good – in 27%, fair in 7%, and poor –in 13%. The most serious problem was the elbow stiffness. Early deep infection was found in 1 patient with type 4B fracture. Ectopic ossification Hastings type I was found in 1 patient. The modern surgical treatment is based on anatomical reduction through fracture type-specific surgical exposure and rigid osteosynthesis. The treatment of choice for irreparable fractures is total elbow arthroplasty (TEA). We discuss the fixation devises, the surgical exposures and the osteosynthesis construct. Our own osteosynthesis preferences are centered around the fixation in the frontal plane and the additional augmentation with sagittal plane implants.

Extracellular Vesicles Derived from Ligament Tissue Transport Interleukin‐17A to Mediate Ligament‐To‐Bone Crosstalk in Ankylosing Spondylitis

AbstractPathological new bone formation is a critical feature of the progression of ankylosing spondylitis (AS), and spine ankylosis is a distinctive feature of this condition. Ligaments are the primary regions of pathological new bone formation in AS. Here, it is demonstrated that ligament tissue‐derived extracellular vesicles (EVs) and their interleukin‐17A (IL‐17A) cargo mediate the communication between the tissue and other cells. The investigation revealed that IL‐17A in EVs can activate the JAK‐STAT3 pathway, thereby stimulating the expression of MMP14 in AS ligament. Overexpression of MMP14 can lead to changes in the cytoskeleton and mechanical signaling of mesenchymal stem cells and other cells. These alterations in cellular cytoskeleton and mechanical signaling at ligament sites in patients with AS or in stem cells treated with EVs can result in pathological new bone formation. Finally, inhibiting IL‐17A activity and EV endocytosis effectively controlled inflammation and pathological new bone formation. Overall, these data suggest that ligament‐derived EVs and the enclosed IL‐17A have a potential role in driving pathological new bone formation in AS, and targeting EVs may therefore emerge as a novel approach to delaying ectopic ossification in AS.

Adipokine dysregulation as an underlying pathology for diffuse ectopic ossification of spinal posterior longitudinal ligament in patients with obesity

BACKGROUND CONTEXTGrowing evidence suggests that obesity is implicated in the progression of heterotopic ossification of the posterior longitudinal ligament of the spine (OPLL), a major cause of myelopathy in Asians. However, it remains unclear whether dysregulation of adipokine production due to fat accumulation contributes to OPLL progression. PURPOSETo determine whether adipose-derived biochemical signals are associated with OPLL development or severity. STUDY DESIGN/SETTINGA nationwide, multicenter, case-control study. PATIENT SAMPLEPatients with symptomatic thoracic OPLL (T-OPLL) who received treatment between June 2017 and March 2021 and 111 controls without OPLL. OUTCOME MEASURESOPLL severity index based on whole-spine computed tomography. METHODSSerum concentrations of adipokines, including leptin (Lep), tumor necrosis factor α (TNFα), and adiponectin (Adpn), as well as the Adpn/Lep ratio—an indicator of adipokine production dysregulation—were compared between the multiple-region OPLL and the single-region OPLL groups. Regression analysis was performed to examine the correlation between adipokine concentrations and OPLL severity index, which was calculated using whole-spine computed tomography images of 77 patients with T-OPLL within 3 years of onset. Using propensity score matching, the adipokine profiles of 59 patients with T-OPLL were compared with those of 59 non-OPLL controls. RESULTSPatients with multiple-region OPLL exhibited a higher body mass index (BMI), lower serum Adpn/Lep ratio, and higher serum concentration of osteocalcin (OCN) than those with single-region OPLL. The OPLL severity index exhibited a weak positive correlation with BMI and serum Lep levels and a weak negative correlation with the Adpn/Lep ratio. Serum TNFα and OCN concentrations were significantly higher in patients with T-OPLL than in controls with similar age, sex, and BMI. CONCLUSIONSPatients with diffuse OPLL over the entire spine are often metabolically obese with low Adpn/Lep ratios. In patients with OPLL, TNFα and OCN serum concentrations were essentially elevated regardless of obesity, suggesting a potential association with OPLL development. Considering the absence of therapeutic drugs for OPLL, the findings presented herein offer valuable insights that can aid in identifying therapeutic targets and formulating strategies to impede its progression.

Dual and opposing role of retinoic acid receptor signaling in mesenchymal stem cells for tendon ossification in mice.

Heterotopic ossification is abnormal bone formation in soft tissues that occurs primarily after injury and major surgery. This condition often causes local pain and limits joint motion in the affected limb. Currently, there is no effective treatment or prophylaxis for this condition other than surgical removal of the lesion. Recent studies suggest that retinoic acid receptor (RAR) agonists are effective in suppressing heterotopic ossification in patients with Fibrodysplasia Ossificans Progressiva, a congenital disorder characterized by progressive ossification of soft tissue, by suppressing the aberrant differentiation of mesenchymal stem cells in muscle. In this study, we aimed to elucidate the potential use of RAR agonists in suppressing injury-induced ectopic tendon ossification using a mouse Achilles tenotomy model. Contrary to our initial hypothesis, administration of RAR agonists throughout the experimental period (5 weeks) accelerated ectopic tendon ossification in our model. Of note, in vitro differentiation experiments using tendon-derived mesenchymal stem cells revealed that RAR agonists play opposing roles in osteogenic and chondrogenic differentiation, promoting the former and suppressing the latter. Indeed, we found that RAR agonists suppressed tendon ossification when administered before cartilage nodule formation, but promoted it when administered after. These results suggest that RAR agonists have a dual and opposing effect on tendon ectopic ossification, depending on the duration and timing of their administration. Our data may provide a basis for further investigation of the potential use of RAR agonists in the treatment of injury-induced heterotopic ossification.

Enpp1 mutations promote upregulation of hedgehog signaling in heterotopic ossification with aging.

Heterotopic ossification of the tendon and ligament (HOTL) is a chronic progressive disease that is usually accompanied by thickening and ossification of ligaments and high osteogenic activity of the surrounding ligament tissue. However, the molecular mechanism of maintaining the cellular phenotype of HOTL remains unclear. We first constructed a model of HOTL, Enpp1flox/flox/EIIa-Cre mice, a novel genetic mouse system. Imaging, histological, and cell-level analyses were performed to investigate the progressive ossification of the posterior longitudinal ligament, Achilles tendons, and degeneration joints caused by Enpp1 deficiency. The results indicate that Enpp1 deficiency led to markedly progressive heterotopic ossification (HO), especially spine, and Achilles tendons, and was associated with progressive degeneration of the knees. The bone mass was decreased in the long bone. Furthermore, fibroblasts from Enpp1flox/flox/EIIa-Cre mice had greater osteogenic differentiation potential following induction by osteogenesis, accompanied by enhanced hedgehog (Hh) signaling. In addition, fibroblast cells show senescence, and aggravation of the senescence phenotype by further osteogenic induction. Our study indicated that with increasing age, mutations in Enpp1 promote ectopic ossification of spinal ligaments and endochondral ossification in tendons and further aggravate knee degeneration by upregulating hedgehog signaling.

Comparison of the posterior hemipelvectomy of the greater trochanter approach with the standard Kocher-Langenbeck approach in the treatment of posterior acetabulum wall fractures

To compare the clinical efficacy of the posterior hemipelvectomy of the greater trochanter approach with the standard Kocher-Langenbeck(K-L) approach in the treatment of posterior acetabulum wall fractures and to explore a more optimal approach for the treatment of posterior acetabulum wall fractures. Total of 26 patients with posterior acetabulum wall fractures were retrospectively analysed and divided into two groups:the posterior hemipelvectomy of the greater trochanter group (test group) and the standard K-L approach group (control group). In the test group, there were 24 patients including 16 males and 8 females with an average age of (42.00±4.52) years old, the time of injury to surgery was (6.75±1.15) d. In the control group, there were 23 patients including 16 males and 7 females with an average age of (41.00±5.82) years old, the time of injury to surgery was (7.09±1.20) days. The total hospital stay, length of incision, operation time, intraoperative bleeding, postoperative drainage, discharge, fracture reduction quality (Matta criteria), hip abduction muscle strength, hip function (Merle d'Aubigne-Postel score), postoperative complications and the incidence of ectopic ossification were compared. All cases were followed up for 6 months. There was no significant difference in incision length, intraoperative bleeding and postoperative drainage between two groups(P>0.05). However, the operation time of the test group was shorter than that of the control group (P<0.05). There was no statistically significant difference in fracture reduction and hip function between two groups (P>0.05). The hip abduction muscle strength of test group was better than that of control group(P<0.05). In addition, there was no significant difference in the incidence of postoperative complications and heterotopic ossification between two groups(P>0.05). Compared with the standard K-L approach, the posterior hemipelvectomy of the greater trochanter approach can shorten the operative time, has better recovery of the postoperative hip abduction muscle strength, exposes the view of the fracture involving the more comminuted posterior acetabulum wall or the fracture of the roof of the socket, improved the rate of fracture anatomical repositioning, provides a new idea for the clinical treatment of posterior acetabulum wall fractures, and allows patients to perform functional exercises at an early stage.

Osteoinductive biomaterials: Machine learning for prediction and interpretation

Biomaterials with osteoinductivity are widely used for bone defect repair due to their unique structures and functions. Machine learning (ML) is pivotal in analyzing osteoinductivity and accelerating new material design. However, challenges include creating a comprehensive database of osteoinductive materials and dealing with low-quality, disparate data. As a standard for evaluating the osteoinductivity of biomaterials, ectopic ossification has been used. This paper compiles research findings from the past thirty years, resulting in a robust database validated by experts. To tackle issues of limited data samples, missing data, and high-dimensional sparsity, a data enhancement strategy is developed. This approach achieved an area under the curve (AUC) of 0.921, a precision of 0.839, and a recall of 0.833. Model interpretation identified key factors such as porosity, bone morphogenetic protein-2 (BMP-2), and hydroxyapatite (HA) proportion as crucial determinants of outcomes. Optimizing pore structure and material composition through partial dependence plot (PDP) analysis led to a new bone area ratio of 14.7 ± 7 % in animal experiments, surpassing the database average of 10.97 %. This highlights the significant potential of ML in the development and design of osteoinductive materials. Statement of significanceThis study leverages machine learning to analyze osteoinductive biomaterials, addressing challenges in database creation and data quality. Our data enhancement strategy significantly improved model performance. By optimizing pore structure and material composition, we increased new bone formation rates, showcasing the vast potential of machine learning in biomaterial design.

Effectiveness of reduction robot combined with navigation robot-assisted minimally invasive treatment for Tile type B pelvic fractures

To explore the effectiveness of reduction robot combined with navigation robot-assisted minimally invasive treatment for Tile type B pelvic fractures. Between January 2022 and February 2023, 10 patients with Tile type B pelvic fractures were admitted. There were 6 males and 4 females with an average age of 45.5 years (range, 30-71 years). The fractures were caused by traffic accident in 5 cases, bruising by heavy object in 3 cases, and falling from height in 2 cases. The interval between injury and operation ranged from 4-13 days (mean, 6.8 days). There were 2 cases of Tile type B1 fractures, 1 case of Tile type B2 fracture, and 7 cases of Tile type B3 fractures. After closed reduction under assistance of reduction robot, the anterior ring was fixed with percutaneous screws with or without internal fixator, and the posterior ring was fixed with sacroiliac joint screws under assistance of navigation robot. The time of fracture reduction assisted by the reduction robot was recorded and the quality of fracture reduction was evaluated according to the Matta scoring criteria. The operation time, intraoperative fluoroscopy frequency and time, intraoperative bleeding volume, and incidence of complications were also recorded. During follow-up, the X-ray film of pelvis was taken to review the fracture healing, and the Majeed score was used to evaluate hip joint function. The time of fracture reduction was 42-62 minutes (mean, 52.3 minutes). The quality of fracture reduction according to the Matta scoring criteria was rated as excellent in 4 cases, good in 5 cases, and poor in 1 case, with excellent and good rate of 90%. The operation time was 180-235 minutes (mean, 215.5 minutes). Intraoperative fluoroscopy was performed 18-66 times (mean, 31.8 times). Intraoperative fluoroscopy time was 16-59 seconds (mean, 28.6 seconds). The intraoperative bleeding volume was 50-200 mL (range, 110.0 mL). No significant vascular or nerve injury occurred during operation. All patients were followed up 13-18 months (mean, 16 months). X-ray films showed that all fractures healed with the healing time of 11-14 weeks (mean, 12.3 weeks). One case of ectopic ossification occurred during follow-up. At last follow-up, the Majeed score was 70-92 (mean, 72.7), and the hip joint function was rated as excellent in 2 cases and good in 8 cases, with the excellent and good rate of 100%. The reduction robot combined with navigation robot-assisted minimally invasive treatment for Tile type B pelvic fractures has the characteristics of intelligence, high safety, convenient operation, and minimally invasive treatment, which can achieve reliable effectiveness.

Ilizarov technique for treating elbow stiffness caused by myositis ossificans: A case report

BACKGROUND Myositis ossificans (MO) is a rare disease involving the formation of bone outside the musculoskeletal system. While surgical intervention is the main treatment approach, preventing recurrence and standardized rehabilitation are also crucial. Here, we present a surgical strategy to prevent the recurrence of MO. CASE SUMMARY A 28-year-old female patient was admitted for the first time for a comminuted fracture of the left olecranon. However, incorrect postoperative rehabilitation resulted in the development of elbow joint stiffness with ectopic ossification, causing a loss of normal range of motion. The patient was diagnosed with MO based on physical examination, X-ray findings, and clinical presentation. We devised a surgical strategy to remove MO, followed by fixation with an Ilizarov frame, and implemented a scientifically reasonable rehabilitation plan. The surgery lasted for 3 h with an estimated blood loss of 45 mL. A drainage tube was placed after surgery, and fluid was aspirated through ultrasound-guided puncture. The patient experienced a significant reduction in joint stiffness after surgery. In the final follow-up at 9 mouths, there was evident improvement in the range of motion of the elbow joint, and no other symptoms were reported. CONCLUSION The Ilizarov frame is an advantageous surgical technique for facilitating rehabilitation after MO removal. It offers benefits such as passive recovery, individualized treatment, and prompt recovery.

Prg4-Expressing Chondroprogenitor Cells in the Superficial Zone of Articular Cartilage.

Joint-resident chondrogenic precursor cells have become a significant therapeutic option due to the lack of regenerative capacity in articular cartilage. Progenitor cells are located in the superficial zone of the articular cartilage, producing lubricin/Prg4 to decrease friction of cartilage surfaces during joint movement. Prg4-positive progenitors are crucial in maintaining the joint's structure and functionality. The disappearance of progenitor cells leads to changes in articular hyaline cartilage over time, subchondral bone abnormalities, and the formation of ectopic ossification. Genetic labeling cell technology has been the main tool used to characterize Prg4-expressing progenitor cells of articular cartilage in vivo through drug injection at different time points. This technology allows for the determination of the origin of progenitor cells and the tracking of their progeny during joint development and cartilage damage. We endeavored to highlight the currently known information about the Prg4-producing cell population in the joint to underline the significance of the role of these cells in the development of articular cartilage and its homeostasis. This review focuses on superficial progenitors in the joint, how they contribute to postnatal articular cartilage formation, their capacity for regeneration, and the consequences of Prg4 deficiency in these cells. We have accumulated information about the Prg4+ cell population of articular cartilage obtained through various elegantly designed experiments using transgenic technologies to identify potential opportunities for further research.

Activation of BMP4/SMAD pathway by HIF-1α in hypoxic environment promotes osteogenic differentiation of BMSCs and leads to ectopic bone formation

ObjectiveHeterotopic ossification (HO), also known as ossifying myositis, is a condition that produces abnormal bone and cartilage tissue in the soft tissues. Hypoxia inducible factor lα (HIF-lα) regulates the expression of various genes, which is closely related to the promotion of bone formation, and Drosophila mothers against decapentaplegic protein (SMAD) mediates the signal transduction in the Bone morphogenetic protein (BMP) signaling pathway, which affects the function of osteoblasts and osteoclasts, and thus plays a key role in the regulation of bone remodeling. We aimed to investigate the mechanism by which HIF-1α induces osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) in a hypoxic environment. MethodsA cellular hypoxia model was constructed to verify the expression of HIF-1α, while alizarin red staining was performed to observe the osteogenic differentiation ability of bone marrow mesenchymal stem cells (BMSCs). Alizarin red staining was used to analyze the late mineralization ability of the cells. Western blot analysis was performed to analyze the expression levels of osteogenesis-related factors OCN, OPN proteins as well as the pathway proteins BMP4, p-Smad1/5/8, and Smad1. We also constructed a rat model of ectopic bone formation, observed ectopic ossification by X-ray, and verified the success of the rat model by ELISA of HIF-1α. HE staining was used to observe the matrix and trabecular structure of bone, and Masson staining was used to observe the collagen and trabecular structure of bone. Immunohistochemistry analyzed the expression of OCN and OPN in ectopic bone tissues, and WB analyzed the expression of pathway proteins BMP4, p-Smad1/5/8 and Smad1 in ectopic bone tissues to verify the signaling pathway of ectopic bone formation. ResultsOur results indicate that hypoxic environment upregulates HIF-1a expression and activates BMP4/SMAD signaling pathway. This led to an increase in ALP content and enhanced expression of the osteogenesis-related factors OCN and OPN, resulting in enhanced osteogenic differentiation of BMSCs. The results of our in vivo experiments showed that rats inoculated with BMSCs overexpressing HIF-1α showed bony structures in tendon tissues, enhanced expression of the bone signaling pathways BMP4 and p-Smad1/5/8, and enhanced expression levels of the osteogenic-related factors OCN and OPN, resulting in the formation of ectopic bone. ConclusionsThese data further suggest a novel mechanistic view that hypoxic bone marrow BMSCs activate the BMP4/SMAD pathway by up-regulating the expression level of HIF-1α, thereby promoting the secretion of osteogenic factors leading to ectopic bone formation.

Exosome MiR-21-5p Upregulated by HIF-1α Induces Adipose Stem Cell Differentiation to Promote Ectopic Bone Formation.

Heterotopic bone occurs after burns, trauma and major orthopedic surgery, which cannot be completely cured by current treatments. The development of new treatments requires more in-depth research into the mechanism of HO. Available evidence suggests that miR-21-5p plays an important role in bone formation. However, its mechanism in traumatic HO is still unclear. First, we identified exosomes extracted from L6 cells using TEM observation of the structure and western blotting detection of the surface marker CD63. Regulation effect of HIF-1α to miR-21-5p was confirmed by q-PCR assay. Then we co-cultured L6 cells with ASCs and performed alizarin red staining and ALP detection. Overexpression of miR-21-5p upregulated BMP4, p-smad1/5/8, OCN and OPN, which suggests the BMP4-smad signaling pathway may be involved in miR-21-5p regulation of osteogenic differentiation of ASCs. Finally in vivo experiments showed that miR-21-5p exosomes promoted ectopic formation in traumatized mice. This study confirms that HIF-1α could modulate miR-21-5p exosomes to promote post-traumatic ectopic bone formation by inducing ASCs cell differentiation. Our study reveals the mechanisms of miR-21-5p in ectopic ossification formation after trauma.

Binocular loupe assisted mini-lateral and medial incisions in lateral position for release of elbow stiffness

To analyze the effectiveness of binocular loupe assisted mini-lateral and medial incisions in lateral position for the release of elbow stiffness. The clinical data of 16 patients with elbow stiffness treated with binocular loupe assisted mini-internal and external incisions in lateral position release between January 2021 and December 2022 were retrospectively analyzed. There were 9 males and 7 females, aged from 19 to 57 years, with a median age of 33.5 years. Etiologies included olecranon fracture in 6 cases, elbow dislocation in 4 cases, medial epicondyle fracture in 2 cases, radial head fracture in 4 cases, terrible triad of elbow joint in 2 cases, supracondylar fracture of humerus in 1 case, coronoid process fracture of ulna in 1 case, and humerus fracture in 1 case, with 5 cases presenting a combination of two etiologies. The duration of symptoms ranged from 5 to 60 months, with a median of 8 months. Preoperatively, 12 cases had concomitant ulnar nerve numbness, and 6 cases exhibited ectopic ossification. The preoperative range of motion for elbow flexion and extension was (58.63±22.30)°, the visual analogue scale (VAS) score was 4.3±1.6, and the Mayo score was 71.9±7.5. Incision lengths for both lateral and medial approaches were recorded, as well as the occurrence of complications. Clinical outcomes were evaluated using Mayo scores, VAS scores, and elbow range of motion both preoperatively and postoperatively. The lateral incision lengths for all patients ranged from 3.0 to 4.8 cm, with an average of 4.1 cm. The medial incision lengths ranged from 2.4 to 4.2 cm, with an average of 3.0 cm. The follow-up duration ranged from 6 to 19 months and a mean of 9.2 months. At last follow-up, 1 patient reported moderate elbow joint pain, and 3 cases exhibited residual mild ulnar nerve numbness. The other patients had no complications such as new heterotopic ossification and ulnar nerve paralysis, which hindered the movement of elbow joint. At last follow-up, the elbow range of motion was (130.44±9.75)°, the VAS score was 1.1±1.0, and the Mayo score was 99.1±3.8, which significantly improved when compared to the preoperative ones ( t=-12.418, P<0.001; t=6.419, P<0.001; t=-13.330, P<0.001). The binocular loupe assisted mini-lateral and medial incisions in lateral position integrated the advantages of traditional open and arthroscopic technique, which demonstrated satisfying safety and effectivity for the release of elbow contracture, but it is not indicated for patients with posterior medial heterolateral heterotopic ossification.

Bone-targeted lipoplex-loaded three-dimensional bioprinting bilayer scaffold enhanced bone regeneration.

Clinical bone-morphogenetic protein 2 (BMP2) treatment for bone regeneration, often resulting in complications like soft tissue inflammation and ectopic ossification due to high dosages and non-specific delivery systems, necessitates research into improved biomaterials for better BMP2 stability and retention. To tackle this challenge, we introduced a groundbreaking bone-targeted, lipoplex-loaded, three-dimensional bioprinted bilayer scaffold, termed the polycaprolactone-bioink-nanoparticle (PBN) scaffold, aimed at boosting bone regeneration. We encapsulated BMP2 within the fibroin nanoparticle based lipoplex (Fibroplex) and functionalized it with DSS6 for bone tissue-specific targeting. 3D printing technology enables customized, porous PCL scaffolds for bone healing and soft tissue growth, with a two-step bioprinting process creating a cellular lattice structure and a bioink grid using gelatin-alginate hydrogel and DSS6-Fibroplex, shown to support effective nutrient exchange and cell growth at specific pore sizes. The PBN scaffold is predicted through in silico analysis to exhibit biased BMP2 release between bone and soft tissue, a finding validated by in vitro osteogenic differentiation assays. The PBN scaffold was evaluated for critical calvarial defects, focusing on sustained BMP2 delivery, prevention of soft tissue cell infiltration and controlled fiber membrane pore size in vivo. The PBN scaffold demonstrated a more than eight times longer BMP2 release time than that of the collagen sponge, promoting osteogenic differentiation and bone regeneration in a calvarial defect animal. Our findings suggest that the PBN scaffold enhanced the local concentration of BMP2 in bone defects through sustained release and improved the spatial arrangement of bone formation, thereby reducing the risk of heterotopic ossification.

Biomechanical effects of endplate sagittal coverage change on cervical disc replacement: a finite element analysis.

In recent years, the number of artificial cervical disc replacements has increased, and paravertebral ectopic ossification is a common complication. Although the exact mechanism is not clear, some studies suggest that it is related to the concentration of tissue stress caused by incomplete coverage of the trailing edge of the endplate. Therefore, this study performed a quantitative analysis to compare the biomechanical effects of different sagittal distances at the posterior edge of the endplate of the upper and lower prosthesis on the cervical spine and to explore the mechanical response of incomplete coverage of the posterior edge of the endplate on the paravertebral tissues. A C2-C7 nonlinear finite element model of the cervical spine was established and validated. Based on the cervical spine model, cervical disc replacement surgery models were constructed with different distances of sagittal distance at the posterior edge of the upper prosthetic endplate (0, 1, 2, 3mm, respectively) and sagittal distance at the posterior edge of the lower prosthetic endplate (1, 2, 3mm, respectively). Each model was subjected to the same 1Nm torque and 73.6N driven compressive load. Range of motion (ROM), intervertebral disc pressure (IDP), facet joint force (FJF), and endplate stress were measured at the cervical surgical and other segments. Compared to the intact cervical spine model, the sagittal distance of the posterior edge of the prosthesis endplate at different distances increased the stress on the intervertebral disc and the capsular joint in the adjacent vertebral body segments to different degrees, especially in extension. In different directions of motion, the posterior margin sagittal distance of the posterior edge of the endplate of the lower prosthesis has a greater mechanical influence on the cervical spine compared to the posterior margin sagittal distance of the posterior edge of the endplate of the upper prosthesis. Compared with the intact model, the biomechanical parameters (ROM, FJF, endplate stress) of the C5-C6 segment increased the most when the sagittal distance of the posterior edge of the endplate of the upper prosthesis was 3mm. Compared with the intact model, the maximum intervertebral disc stress of C4-C5 and C6-C7 was 0.57MPa and 0.53MPa, respectively, when the sagittal distance of the posterior edge of the upper prosthetic endplate was 3mm. After the sagittal distance of the posterior edge of the prosthetic endplate was completely covered, the mechanical influence of the entire cervical spine was low. The sagittal distance at the posterior edge of the endplate of different sizes changed the motion pattern and load distribution of the implanted segment to some extent. When the sagittal distance between the prosthesis and the upper endplate was greater than or equal to 3mm, the mechanical indices of the implanted segment increased significantly, increasing the risk of local tissue injury, especially during extension motion. Compared to the sagittal distance at the posterior edge of the endplate of the lower prosthesis, increasing the sagittal distance at the posterior edge of the endplate of the upper prosthesis has a greater effect on the mechanics of the cervical spine.

The IL-17-IL-17RA axis is required to promote osteosarcoma progression in mice

Osteosarcoma is rare but is the most common bone tumor. Diagnostic tools such as magnetic resonance imaging development of chemotherapeutic agents have increased the survival rate in osteosarcoma patients, although 5-year survival has plateaued at 70%. Thus, development of new treatment approaches is needed. Here, we report that IL-17, a proinflammatory cytokine, increases osteosarcoma mortality in a mouse model with AX osteosarcoma cells. AX cell transplantation into wild-type mice resulted in 100% mortality due to ectopic ossification and multi-organ metastasis. However, AX cell transplantation into IL-17-deficient mice significantly prolonged survival relative to controls. CD4-positive cells adjacent to osteosarcoma cells express IL-17, while osteosarcoma cells express the IL-17 receptor IL-17RA. Although AX cells can undergo osteoblast differentiation, as can patient osteosarcoma cells, IL-17 significantly inhibited that differentiation, indicating that IL-17 maintains AX cells in the undifferentiated state seen in malignant tumors. By contrast, IL-17RA-deficient mice transplanted with AX cells showed survival comparable to wild-type mice transplanted with AX cells. Biopsy specimens collected from osteosarcoma patients showed higher expression of IL-17RA compared to IL-17. These findings suggest that IL-17 is essential to maintain osteosarcoma cells in an undifferentiated state and could be a therapeutic target for suppressing tumorigenesis.

Association between serum interleukin-17 levels and ectopic bone formation in OPLL patients with DISH.

To investigate the relationship between the severity and morphology of heterotopic ossification in the spinal ligaments including sacroiliac (SI) joints, and serum interleukin-17 (IL-17) levels in patients with ossification of the posterior longitudinal ligament (OPLL) with or without diffuse idiopathic skeletal hyperostosis (DISH), as well as a non-OPLL group. A total of 103 patients with OPLL [DISH (-), n = 50; DISH (+), n = 53] and 53 age- and gender-matched controls were included. The serum levels of IL-17 were analysed, and the severity of ectopic ossification and the morphology of ectopic bone formation were evaluated. The SI joint morphological variations were categorized into four types. No significant differences were found in serum IL-17 levels between the OPLL and control groups. However, the DISH (+) group showed higher IL-17 levels than the DISH (-) group, especially in female patients (P = 0.003). Additionally, IL-17 levels were positively correlated with the number of flat vertebral units, this being one of the characteristic DISH ossification types (R2 = 0.199, P = 0.012). IL-17 levels in the type showing bridging osteophyte and bone fusion were significantly higher in the DISH (+) group than in the DISH (-) group. The morphological characteristics of paravertebral bone formation in the entire spine, including the SI joint, are likely associated with serum IL-17 levels in OPLL. These findings provide pathological and serological evidence of local inflammation contributing to paravertebral ossification of OPLL patients.