Investigational regenerative medicine for non-traumatic osteonecrosis of the femoral head: a survey of registered clinical trials.

INTRODUCTION: Osteonecrosis of the femoral head (ONFH) is a refractory disease requiring joint replacement in young patients. Regenerative therapies have been developed. AREAS COVERED: This study surveyed clinical trials on regenerative medicine for ONFH. We extracted clinical trials on non-traumatic ONFH from the websites of five publicly available major registries (EuropeanUnion Clinical Trials Register ([EU-CTR],ClinicalTrials.gov, Chinese ClinicalTrial Registry [ChiCTR], University Hospital Medical InformationNetwork - Clinical Trial Registry [UMIN-CTR] and Australian New Zealand Clinical Trials Registry [ANZCTR]).The trials were classified into six categories based on purpose: surgical treatment, non-drug conservative treatment, conservative drug treatment, therapeutic strategy, diagnosis and pathogenesis, and regenerative therapy.) We extracted 169 clinical trials on ONFH. Of these, 37 were on regenerative medicine, including 29 on cell therapy. Surgical treatment was the most common treatment, followed by regenerative therapy.There were 9 clinical trials registered in the EU-CTR, with 5 on regenerative medicine; 79 trials registered on ClinicalTrials.gov, with 24 on regenerativemedicine; 54 trials registered in the ChiCTR, with 6 on regenerative medicine. EXPERT OPINION: The focus of the joint-preserving surgery has shifted to regenerative therapy based on using cell therapy in early-stage ONFH. The global standardisation of regenerative therapy is still ongoing.

Evaluating blood supply changes in the osteonecrosis of the femoral head using gadobutrol-based steady-state MR angiography.

OBJECTIVES: Assess the feasibility of using gadobutrol-based steady-state (SS) MR angiography (MRA) to evaluate the blood supply changes of osteonecrosis of the femoral head (ONFH). MATERIALS AND METHODS: Participants were recruited in this prospective study from December 2021 to May 2022 in a single center. The number of superior retinacular arteries (SRAs), inferior retinacular arteries (IRAs), anterior retinacular arteries (ARAs), and overall retinacular arteries (ORAs), as well as the affected rates of SRA and IRA, were determined and compared between healthy and ONFH hips and between hips across the Association Research Circulation Osseous (ARCO) staging I-IV. RESULTS: Twenty healthy and 64 ONFH hips were evaluated in 54 participants. There were significant differences between ARCO I-IV for the number of ORAs (mean of 3.5, 2.3, 1.7, and 0.8 for ARCO I-IV, respectively; p < .001), SRAs (median of 2.5, 1, 0.5, and 0 for ARCO I-IV, respectively; p < .001), and the affected rate of SRAs (20.00%, 65.22%, 77.78%, 92.31% for ARCO I-IV, respectively, p = 0.002). There were significant differences between ONFH and healthy hips for the number of ORAs (median of 5 vs. 2; p < .001), SRAs (median of 3 vs. 1; p < .001), IRAs (median of 1 vs. 1; p < .001), ARAs (median of 0 vs. 0; p = 0.04), and also the affected rate of SRAs (5.00% vs. 67.20%, p < .001) and IRAs (30% vs. 84.4%, p < .001). CONCLUSION: Gadobutrol-enhanced SS MRA is a feasible method for evaluation of hemodynamics in ONFH. CLINICAL RELEVANCE STATEMENT: Gadobutrol-enhanced magnetic resonance angiography can evaluate blood supply changes of ONFH and therefore helps to aid in the diagnosis and guide treatment of ONFH. KEY POINTS: • Gadobutrol-enhanced magnetic resonance angiography showed changes in the retinacular artery related to the severity of femoral osteonecrosis. • Gadobutrol-enhanced magnetic resonance angiography revealed a reduced blood supply to the ischemic necrotic femoral head compared to the healthy counterparts.

Bone marrow edema of the hip: a narrative review.

Bone marrow edema (BME) of the hip is a radiological-clinical condition with symptoms ranging from asymptomatic to severe, and it is characterized by increased interstitial fluid within the bone marrow, usually at the femur. Depending on the etiology it can be classified as primary or secondary. The primary cause of BME is unknown, while the secondary forms include traumatic, degenerative, inflammatory, vascular, infectious, metabolic, iatrogenic, and neoplastic etiologies. BME could be classified as reversible or progressive. Reversible forms include transient BME syndrome and regional migratory BME syndrome. Progressive forms include avascular necrosis of the femoral head (AVNH), subchondral insufficiency fracture, and hip degenerative arthritis. The diagnosis can be difficult, because at the beginning, the outbreak of hip pain, typically acute and disabling without any prior trauma or exceptional physical activity, is poorly supported by radiographic findings. MRI is the gold standard, and it shows an area of intermediate signal on T1-weighted MRI scans and a high signal on T2-weighted scans, usually lacking sharps margins. In the reversible form, BME is typically self-limiting, and it can be managed conservatively by means of pharmacological and physical therapy. Surgery is generally required for progressive forms in patients who failed non-operative treatment, and it ranges from femoral head and neck core decompression to total hip arthroplasty.

Radiological manifestation of avascular necrosis (AVN) in sickle cell disease (SCD): a review of diagnostic imaging.

Symptomatic avascular necrosis (AVN) imposes a higher risk for acute care consumption in adults living with SCD. Symptomatic AVN, have higher rates of visits to the emergency department, higher rates of admissions, and longer lengths of stay in hospitals. Properly timed diagnosis and early interventions can reduce morbidity and enhance the quality of life in these patients. Vaso-occlusion secondary to sickling leads to osteonecrosis of the joint/bone (AVN, dactylitis) and invites infection (osteomyelitis and septic arthritis). Understanding and awareness of the imaging features related to this major morbidity complication are essential for early diagnosis and prompt management. In about half of the patients with SCD, AVN can lead to chronic pain, particularly in the head of the femur and humerus. Humeral and femoral head AVN tend to be linked with each other.  Vertebral bone compression and collapse secondary to AVN have also been reported.  The diagnosis of AVN must be accurate, as the condition is complex requiring specific treatment according to the grade of bone and joint involvement. There are several classifications or staging systems used for grading bone and joint involvement. Knowledge of the image patterns and grade of affection in different joints and bones and the degree of progression of AVN lesions can markedly improve management decisions on AVN-specific surgical versus non-surgical interventions and improve patient outcomes. The aim of this report is to summarize the different imaging techniques and their role in the proper/early diagnosis and follow up of patients with AVN with detailed examples of the common sites involved.

Femoral head avascular necrosis in COVID-19 survivors: a systematic review.

The current systematic review aimed to document published cases of femoral head avascular necrosis (FHAVN) post-COVID-19, to report the COVID-19 disease characteristics and management patients received, and to evaluate how the FHAVN were diagnosed and treated among various reports. A systematic literature review was performed per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines through a comprehensive English literature search on January 2023 through four databases (Embase, PubMed, Cochrane Library, and Scopus), including studies reporting on FHAVN post-COVID-19. Fourteen articles were included, ten (71.4%) were case reports, and four (28.6%) case series reported on 104 patients having a mean age of 42.2 ± 11.7 (14:74) years, in which 182 hip joints were affected. In 13 reports, corticosteroids were used during the COVID-19 management plan for a mean of 24.8 ± 11 (7:42) days, with a mean prednisolone equivalent dose of 1238.5 ± 492.8 (100:3520) mg. A mean of 142.1 ± 107.6 (7:459) days passed between COVID-19 diagnosis and FHAVN detection, and most of the hips were stage II (70.1%), and concomitant septic arthritis was present in eight (4.4%) hips. Most hips (147, 80.8%) were treated non-surgically, of which 143 (78.6%) hips received medical treatment, while 35 (19.2%) hips were surgically managed, 16 (8.8%) core decompression, 13 (7.1%) primary THA, five (2.7%) staged THA and three (1.6%) had first stage THA (debridement and application of antibiotic-loaded cement spacer). The outcomes were acceptable as regards hip function and pain relief. Femoral head avascular necrosis post-COVID-19 infection is a real concern, primarily attributed to corticosteroid usage, besides other factors. Early suspicion and detection are mandatory, as conservative management lines are effective during early stages with acceptable outcomes. However, surgical intervention was required for progressive collapse or patients presented in the late stage.

Runx2 overexpression promotes bone repair of osteonecrosis of the femoral head (ONFH).

BACKGROUND: Runt-related transcription factor-2 (Runx2) has been considered an inducer to improve bone repair ability of mesenchymal stem cells (MSCs). METHODS AND RESULTS: Twenty-four rabbits were used to establish Osteonecrosis of the femoral head (ONFH) and randomly devided into four groups: Adenovirus Runx2 (Ad-Runx2) group, Runx2-siRNA group, MSCs group and Model group. At 1 week after model establishment, the Ad-Runx2 group was treated with 5 × 107 MSCs transfected through Ad-Runx2, the Runx2-siRNA group was treated with 5 × 107 MSCs transfected through Runx2-siRNA, the MSCs group was injected with 5 × 107 untreated MSCs, and the Model group was treated with saline. The injection was administered at 1 week and 3 weeks after model establishment. The expression of bone morphogenetic protein 2 (BMP-2), Runx2 and Osterix from the femoral head was detected at 3 and 6 weeks after MSCs being injected, and Masson Trichrome Staining, Gross Morphology, X-ray and CT images observation were used to evaluate the repair effect of ONFH. The data revealed that the expression of BMP-2, Runx2 and Osterix in the Runx2-siRNA group was reduced at 3 weeks compared with the MSCs group, and then the expression further reduced at 6 weeks, but was still higher than the Model group besides Osterix; The expression of these three genes in the Ad-Runx2 group was higher than in the MSCs group. Masson Trichrome Staining, Gross Morphology and X-ray and CT images observation revealed that necrotic femoral head of the MSCs group was more regular and smooth than the Runx2-siRNA group, which has a collapsed and irregular femoral head. In the Ad-Runx2 group, necrotic femoral head was basically completely repaired and covered by rich cartilage and bone tissue. CONCLUSIONS: Overexpression of Runx2 can improve osteoblastic phenotype maintenance of MSCs and promote necrotic bone repair of ONFH.

LncAABR07053481 inhibits bone marrow mesenchymal stem cell apoptosis and promotes repair following steroid-induced avascular necrosis.

The osteonecrotic area of steroid-induced avascular necrosis of the femoral head (SANFH) is a hypoxic microenvironment that leads to apoptosis of transplanted bone marrow mesenchymal stem cells (BMSCs). However, the underlying mechanism remains unclear. Here, we explore the mechanism of hypoxic-induced apoptosis of BMSCs, and use the mechanism to improve the transplantation efficacy of BMSCs. Our results show that the long non-coding RNA AABR07053481 (LncAABR07053481) is downregulated in BMSCs and closely related to the degree of hypoxia. Overexpression of LncAABR07053481 could increase the survival rate of BMSCs. Further exploration of the downstream target gene indicates that LncAABR07053481 acts as a molecular "sponge" of miR-664-2-5p to relieve the silencing effect of miR-664-2-5p on the target gene Notch1. Importantly, the survival rate of BMSCs overexpressing LncAABR07053481 is significantly improved after transplantation, and the repair effect of BMSCs in the osteonecrotic area is also improved. This study reveal the mechanism by which LncAABR07053481 inhibits hypoxia-induced apoptosis of BMSCs by regulating the miR-664-2-5p/Notch1 pathway and its therapeutic effect on SANFH.

Application of biomaterials in treating early osteonecrosis of the femoral head: Research progress and future perspectives.

Osteonecrosis of the femoral head (ONFH), a progressive pathological process of femoral head ischemia and osteocyte necrosis, is a refractory orthopedic disease caused by multiple etiologies and there is no complete cure at present. With the extension of ONFH duration, osteocyte apoptosis and trabecular bone loss can decrease the load-bearing capacity of the femoral head, which leads to the collapse of the articular cartilage and subchondral bone. Therefore, an urgent clinical need exists to develop effective treatment strategies of early-stage ONFH for maintaining the hip joint function and preventing femoral head collapse. In recent years, extensive attention has been paid to the application of diverse biomaterials in treating early ONFH for sustaining the normal morphology and function of the autologous femoral head, and slowing disease progression. Herein, we review the research progress of bone grafts, metallic materials, bioceramics, bioglasses and polymer materials for early ONFH treatment, and discuss the biological mechanisms of bone repair and regeneration in the femoral-head necrotic area. We propose suggestions for future research directions, from a special perspective of improving the local microenvironment in femoral head by facilitating vessel-associated osteoclasts (VAOs) generation and coupling of bone-specific angiogenesis and osteogenesis, as well as inhibiting bone-associated osteoclasts (BAOs) and BAO-mediated bone resorption. This review can provide ideas for the research, development, and clinical application of biomaterials for treating early ONFH. STATEMENT OF SIGNIFICANCE: We believe that at least three aspects of this manuscript make it interesting to readers of the Acta Biomaterialia. First, we briefly summarize the incidence, pathogenesis, risk factors, classification criteria and treatment of early osteonecrosis of the femoral head (ONFH). Second, we review the research progress in biomaterials for early ONFH treatment and the biological mechanisms of bone repair and regeneration in femoral-head necrotic area. Third, we propose future research progress on improving the local microenvironment in femoral head by facilitating vessel-associated osteoclasts generation and coupling of bone-specific angiogenesis and osteogenesis, as well as inhibiting bone-associated osteoclasts and bone resorption. We hope this review can provide ideas for the research, development, and clinical application of biomaterials for treating early ONFH.

Prognosis of hip osteonecrosis after cell therapy with a calculator and artificial intelligence: ten year collapse-free survival prediction on three thousand and twenty one hips.

PURPOSE: Several reports have identified prognostic factors for hip osteonecrosis treated with cell therapy, but no study investigated the accuracy of artificial intelligence method such as machine learning and artificial neural network (ANN) to predict the efficiency of the treatment. We determined the benefit of cell therapy compared with core decompression or natural evolution, and developed machine-learning algorithms for predicting ten year collapse-free survival in hip osteonecrosis treated with cell therapy. Using the best algorithm, we propose a calculator for "prognosis hip osteonecrosis cell therapy (PHOCT)" accessible for clinical use. METHODS: A total of 3145 patients with 5261 osteonecroses without collapses were included in this study, comprising 1321 (42%) men and 1824 (58%) women, with a median age of 34 (12-62) years. Cell therapy was the treatment for 3021 hips, core decompression alone for 1374 hips, while absence of treatment was the control group of 764 hips. First, logistic regression and binary logistic regression analysis were performed to compare results of the three groups at ten years. Then an artificial neural network model was developed for ten year collapse-free survival after cell therapy. The models' performances were compared. The algorithms were assessed by calibration, and performance, and with c-statistic as measure of discrimination. It ranges from 0.5 to 1.0, with 1.0 being perfect discrimination and 0.5 poor (no better than chance at making a prediction). RESULTS: Among the 3021 hips with cell therapy, 1964 hips (65%) were collapse-free survival at ten years, versus 453 (33%) among those 1374 treated with core decompression alone, and versus 115 (15%) among 764 hips with natural evolution. We analyzed factors influencing the prediction of collapse-free period with classical statistics and artificial intelligence among hips with cell therapy. After selecting variables, a machine learning algorithm created a prognosis osteonecrosis cell therapy calculator (POCT). This calculator proved to have good accuracy on validation in these series of 3021 hip osteonecroses treated with cell therapy. The algorithm had a c-statistic of 0.871 suggesting good-to-excellent discrimination when all the osteonecroses were mixed. The c-statistics were calculated separately for subpopulations of categorical osteonecroses. It retained good accuracy, but underestimated ten year survival in some subgroups, suggesting that specific calculators could be useful for some subgroups. This study highlights the importance of multimodal evaluation of patient parameters and shows the degree to which the outcome is modified by some decisions that are within a surgeon's control, as the number of cells to aspirate, the choice of injecting in both the osteonecrosis and the healthy bone, the choice between unilateral or bilateral injection, and the possibility to do a repeat injection. CONCLUSION: Many disease conditions and the heterogeneities of patients are causes of variation of outcome after cell therapy for osteonecrosis. Predicting therapeutic effectiveness with a calculator allows a good discrimination to target patients who are most likely to benefit from this intervention.

Notch-RBPJ Pathway for the Differentiation of Bone Marrow Mesenchymal Stem Cells in Femoral Head Necrosis.

Femoral head necrosis (FHN) is a common leg disease in broilers, resulting in economic losses in the poultry industry. The occurrence of FHN is closely related to the decrease in the number of bone marrow mesenchymal stem cells (BMSCs) and the change in differentiation direction. This study aimed to investigate the function of differentiation of BMSCs in the development of FHN. We isolated and cultured BMSCs from spontaneous FHN-affected broilers and normal broilers, assessed the ability of BMSCs into three lineages by multiple staining methods, and found that BMSCs isolated from FHN-affected broilers demonstrated enhanced lipogenic differentiation, activated Notch-RBPJ signaling pathway, and diminished osteogenic and chondrogenic differentiation. The treatment of BMSCs with methylprednisolone (MP) revealed a significant decrease in the expressions of Runx2, BMP2, Col2a1 and Aggrecan, while the expressions of p-Notch1/Notch1, Notch2 and RBPJ were increased significantly. Jagged-1 (JAG-1, Notch activator)/DAPT (γ-secretase inhibitor) could promote/inhibit the osteogenic or chondrogenic ability of MP-treated BMSCs, respectively, whereas the differentiation ability of BMSCs was restored after transfection with si-RBPJ. The above results suggest that the Notch-RBPJ pathway plays important role in FHN progression by modulating the osteogenic and chondrogenic differentiation of BMSCs.

Connexin43 overexpression promotes bone regeneration by osteogenesis and angiogenesis in rat glucocorticoid-induced osteonecrosis of the femoral head.

Glucocorticoids induced osteonecrosis of the femoral head (GIONFH) is a devastating orthopedic disease. Previous studies suggested that connexin43 is involved in the process of osteogenesis and angiogenesis. However, the role of Cx43 potentiates in the osteogenesis and angiogenesis of bone marrow-derived stromal stem cells (BMSCs) in GIONFH is still not investigated. In this study, BMSCs were isolated and transfected with green fluorescent protein or the fusion gene encoding GFP and Cx43. The osteogenic differentiation of BMSCs were detected after transfected with Cx43. In addition, the migration abilities and angiogenesis of human umbilical vein endothelial cells (HUVECs) were been detected after induced by transfected BMSCs supernatants in vitro. Finally, we established GC-ONFH rat model, then, a certain amount of transfected or controlled BMSCs were injected into the tibia of the rats. Immunohistological staining and micro-CT scanning results showed that the transplanted experiment group had significantly promoted more bone regeneration and vessel volume when compared with the effects of the negative or control groups. This study demonstrated for the first time that the Cx43 overexpression in BMSCs could promote bone regeneration as seen in the osteogenesis and angiogenesis process, suggesting that Cx43 may serve as a therapeutic gene target for GIONFH treatment.

MsgeCNN: Multiscale geometric embedded convolutional neural network for ONFH segmentation and grading.

BACKGROUND: The incidence of osteonecrosis of the femoral head (ONFH) is increasing gradually, rapid and accurate grading of ONFH is critical. The existing Steinberg staging criteria grades ONFH according to the proportion of necrosis area to femoral head area. PURPOSE: In the clinical practice, the necrosis region and femoral head region are mainly estimated by the observation and experience of doctor. This paper proposes a two-stage segmentation and grading framework, which can be used to segment the femoral head and necrosis, as well as to diagnosis. METHODS: The core of the proposed two-stage framework is the multiscale geometric embedded convolutional neural network (MsgeCNN), which integrates geometric information into the training process and accurately segments the femoral head region. Then, the necrosis regions are segmented by the adaptive threshold method taking femoral head as the background. The area and proportion of the two are calculated to determine the grade. RESULTS: The accuracy of the proposed MsgeCNN for femoral head segmentation is 97.73%, sensitivity is 91.17%, specificity is 99.40%, dice score is 93.34%. And the segmentation performance is better than the existing five segmentation algorithms. The diagnostic accuracy of the overall framework is 90.80%. CONCLUSIONS: The proposed framework can accurately segment the femoral head region and the necrosis region. The area, proportion, and other pathological information of the framework output provide auxiliary strategies for subsequent clinical treatment.

The effects of nano-hydroxyapatite/polyamide 66 scaffold on dog femoral head osteonecrosis model: a preclinical study.

The lack of mechanical support in the bone tunnel formed after CD often results in a poor therapeutic effect in ONFH. The n-HA/P66 has excellent biocompatibility and mechanical properties and has been widely used in bone regeneration. The present study aimed to evaluate the effects of n-HA/P66 scaffold treatment in a dog model of ONFH. A FEA was performed to analyze the mechanical changes in the femoral head after CD and n-HA/P66 scaffold or tantalum rod implantation. Fifteen male beagles were selected to establish the model of ONFH by liquid nitrogen freezing method, and the models were identified by x-ray and MRI 4 weeks after modeling and randomly divided into three groups. Nine weeks later, femoral head samples were taken for morphology, micro-CT, and histological examination. The FEA showed that the n-HA/P66 scaffold proved the structural support in the bone tunnel, similar to the tantalum rod. The morphology showed that the femoral head with n-HA/P66 implantation is intact, while the femoral heads in the model group and CD group are collapsing. Moreover, the micro-CT results of the n-HA/P66 scaffold group were better than the model group and the CD group, and the interface between the n-HA/P66 scaffold and bone tissue is blurred. Furthermore, the histological result also verifies the alterations in micro-CT, and bone tissue grows in the bone tunnel with n-HA/P66 scaffold implanted while few in the CD group. The CD results in a lack of mechanical support in the femoral head subchondral bone and bone tunnel high stress. The n-HA/P66 scaffold implantation can provide mechanical support and relieve high stress induced by CD. The n-HA/P66 scaffold can treat femoral head necrosis and provide the bone tissue growth scaffold for the femoral head after CD to promote bone tissue regeneration.

Prognostic factors in the management of osteonecrosis of the femoral head: A systematic review.

BACKGROUND: Several hip preserving techniques have been described for the management of osteonecrosis of the femoral head (ONFH). This systematic review identified prognostic factors in the treatment of ONFH that are associated with treatment failure and conversion to total hip arthroplasty (THA). MATERIAL AND METHODS: This study followed the PRISMA guidelines. The literature search was conducted in November 2021. All clinical trials comparing two or more treatments for femoral head osteonecrosis were accessed. A multivariate analysis was performed to investigate the association between baseline characteristics and the surgical outcome. A multiple linear model regression analysis through the Pearson Product-Moment Correlation Coefficient (r) was used. RESULTS: Data from 88 articles (6112 procedures) were retrieved. Female gender was associated with increased time to THA (P = 0.03) and reduced rate of THA (P = 0.03). Longer symptom duration before treatment was associated with shorter time to failure (P = 0.03). Increased pre-treatment VAS was associated with reduced time to failure (P = 0.03) and time to THA (P = 0.04). Reduced pre-treatment hip function was associated with increased rate of THA (P = 0.02) and failure (P = 0.005). Patient age and BMI, aetiology, time from surgery to full weight bearing and the side did not show evidence of a statistically significant association with the surgical outcome. CONCLUSION: Male gender, longer symptom duration before treatment, higher VAS scores, and lower HHS scores were negative prognostic factors after treatment for osteonecrosis of the femoral head.

Diagnosis and treatment of avascular necrosis of the humeral head: Current concepts.

Avascular necrosis (AVN) of the humeral head is an uncommon clinical entity which can result in significant morbidity for patients. There is a paucity of literature concerning humeral head AVN, which may be due to the relatively rarity of the condition and poorly understood nature. Despite being first described decades ago, the underlying pathophysiology leading to humeral head AVN is still poorly defined. While the staging of humeral head AVN is well described, not much is known about prognosticating factors to predict the eventual course. Most of the management options are based on that of femoral head AVN, and even so, there is a paucity of good quality clinical trials in the literature. This current concepts paper describes what is known about humeral head AVN and proposes a management algorithm to guide clinicians.

Insight into Steroid-Induced ONFH: The Molecular Mechanism and Function of Epigenetic Modification in Mesenchymal Stem Cells.

Osteonecrosis of the femoral head (ONFH) is a common refractory orthopedic disease, which is one of the common causes of hip pain and dysfunction. ONFH has a very high disability rate, which is associated with a heavy burden to patients, families, and society. The pathogenesis of ONFH is not completely clear. At present, it is believed that it mainly includes coagulation dysfunction, abnormal lipid metabolism, an imbalance of osteogenic/adipogenic differentiation, and poor vascularization repair. The prevention and treatment of ONFH has always been a great challenge for clinical orthopedic surgeons. However, recent studies have emphasized that the use of mesenchymal stem cells (MSCs) to treat steroid-induced ONFH (SONFH) is a promising therapy. This review focuses on the role and molecular mechanism of epigenetic regulation in the progress of MSCs in the treatment of SONFH, and discusses the significance of the latest research in the treatment of SONFH from the perspective of epigenetics.

An overview of pathophysiology and treatment options of osteonecrosis of femoral head in sickle cell disease.

Osteonecrosis of the femoral head (ONFH) is the most prevalent musculoskeletal pathologic manifestation of sickle cell disease (SCD) resulting in an osteonecrotic event. This review aimed to summarize mechanisms involved in pathophysiology of ONFH and treatment options available in Saudi Arabia to treat SCD patients with complication of osteonecrotic event. The pathophysiology of ONFH include genetic and micro particles involvement. The progression of osteonecrosis involves reduced levels of bioactive compounds in peripheral blood mononuclear cells and elevated CD4+T circulating levels to stimulate pro-inflammatory cytokines contributing to inflammation at target site. Initial treatment approach is pharmacological agents use to mitigate risk. Further, bone morphogenetic protein stimulation initiate bone formation and treatment can be improved with the use of bone morphogenetic protein, total hip arthroplasty and cell therapies. This review provides baseline information for future studies to be carried out in Saudi Arabia to improve treatment options in SCD patients with ONFH.

[Expert consensus on clinical diagnosis and treatment technique of osteonecrosis of the femoral head (2022 version)].

Osteonecrosis of the femoral head (ONFH) is a common and refractory disease in the clinic. Although the exact pathophysiological mechanism is not fully understood, it is believed to be closely related to the interruption of intra-bone circulation and eventual bone tissue death. The prevention and treatment of ONFH is always a great challenge for orthopedists. The diagnostic level of ONFH has been continuously improved with the development of imaging techniques such as MRI and the in-depth understanding of the disease in recent years.There are many treatment methods for ONFH, which are generally considered individually and comprehensively according to factors such as the patient's age, osteonecrosis stage, classification, and compliance with joint-sparing treatment. There is currently no unified standard. ONFH staging and classification play an important reference value for doctors to choose treatment options. In recent years, based on the characteristics of ONFH in Chinese people, the academic community has proposed Chinese staging and China-Japan Friendship Hospital (CJFH) classification. The consensus also introduces them together with the international Association Research Circulation Osseous (ARCO) staging to provide guidance for individualized treatment of ONFH. In order to further standardize the diagnosis of ONFH and expand the treatment of ONFH, the Association Related to Circulation Osseous, Chinese Microcirculation Society (CSM-ARCO) organized domestic experts in the field of ONFH to jointly formulate the expert consensus, in order to provide reference for the standardized diagnosis of ONFH and the selection of individualized diagnosis and treatment techniques.

Clinical Application of Shock Wave in the Treatment of Avascular Necrosis of the Femoral Head in the Early and Middle Stages.

In order to observe the clinical efficacy of shock waves in the treatment of avascular necrosis of the femoral head in the early and middle stages, a clinical application method of a shock wave in the treatment of avascular necrosis of the femoral head in the early and middle stages was proposed. The method combines the CT image segmentation technology to further segment the hip joint image, thereby speeding up the treatment speed and achieving a better treatment effect. Experimental results show that CT image segmentation takes 10.9 hours with an average time of 8 seconds, which is faster than other methods. The shock wave is an effective treatment method for early avascular necrosis of the femoral head, and this method will become one of the main methods for the clinical treatment of this kind of disease.

Bone marrow mesenchymal stem cells-derived exosomes mediate nuclear receptor coactivator-3 expression in osteoblasts by delivering miR-532-5p to influence osteonecrosis of the femoral head development.

Exosomes (Exo) originated from bone marrow mesenchymal stem cells (BMSCs) have therapeutic impacts on osteonecrosis of the femoral head (ONFH), and microRNA (miR)-532-5p has been confirmed to participate in ONFH progression. In the research, it was figured out whether BMSCs-Exo could relieve ONFH by delivering miR-532-5p. MG-63 cells were treated with DEX to construct an ONFH cell model in vitro. The effects of Exo and miR-532-5p on the cell viability, lactate dehydrogenase (LDH) content, and apoptosis of BMSCs were detected. The ONFH rat model was established, and the effect of BMSCs-Exo delivering miR-532-5p on the pathological damage of ONFH rats was evaluated. Changes in nuclear receptor coactivator-3 (NCOA3) and apoptotic proteins were assessed by western blot. The relationship between miR-532-5p and NCOA3 was verified by dual luciferase reporter experiments. miR-532-5p was elevated in vivo and in vitro ONFH-models, while NCOA3 expression was reduced. Overexpression of miR-532-5p aggravated DEX toxicity in osteoblasts, decreased cell viability, and promoted apoptosis. Knockdown of miR-532-5p made Exo further attenuate the toxic effect of DEX on osteoblasts and inhibited apoptosis. The protective effect of miR-532-5p-delivering Exo on osteoblasts was reversed by NCOA3 silencing. In addition, in vivo experiments also confirmed that knockdown of miR-532-5p enhanced the therapeutic effect of Exo on ONFH rats. This study demonstrates that miR-532-5p-delivering BMSCs-Exo inhibits osteoblast viability and promote apoptosis by targeting NCOA3, thereby aggravating ONFH development.