The 2021 Association Research Circulation Osseous Classification for Early-Stage Osteonecrosis of the Femoral Head to Computed Tomography-Based Study.

BACKGROUND: The Association Research Circulation Osseous developed a novel classification for early-stage (precollapse) osteonecrosis of the femoral head (ONFH). We hypothesized that the novel classification is more reliable and valid when compared to previous 3 classifications: Steinberg, modified Kerboul, and Japanese Investigation Committee classifications. METHODS: In the novel classification, necrotic lesions were classified into 3 types: type 1 is a small lesion, where the lateral necrotic margin is medial to the femoral head apex; type 2 is a medium-sized lesion, with the lateral necrotic margin being between the femoral head apex and the lateral acetabular edge; and type 3 is a large lesion, which extends outside the lateral acetabular edge. In a derivation cohort of 40 early-stage osteonecrotic hips based on computed tomography imaging, reliabilities were evaluated using kappa coefficients, and validities to predict future femoral head collapse by chi-squared tests and receiver operating characteristic curve analyses. The predictability for future collapse was also evaluated in a validation cohort of 104 early-stage ONFH. RESULTS: In the derivation cohort, interobserver reliability (k = 0.545) and intraobserver agreement (63%-100%) of the novel method were higher than the other 3 classifications. The novel classification system was best able to predict future collapse (P < .05) and had the best discrimination between non-progressors and progressors in both the derivation cohort (area under the curve = 0.692 [0.522-0.863], P < .05) and the validation cohort (area under the curve = 0.742 [0.644-0.841], P = 2.46 × 10-5). CONCLUSION: This novel classification is a highly reliable and valid method of those examined. Association Research Circulation Osseous recommends using this method as a unified classification for early-stage ONFH. LEVEL OF EVIDENCE: Level III, diagnostic study.

ARCO Consensus on the Pathogenesis of Non-traumatic Osteonecrosis of the Femoral Head.

Osteonecrosis of the femoral head (ONFH) is a devastating disease frequently leading to femoral head collapse and hip arthritis. Specifically, non-traumatic ONFH primarily affects young and middle-aged adults. Although compromised local circulation of the femoral head seems to be pathognomonic for the disease, the pathogenesis is perplexing and continues to be an area of scrutiny and research. Comprehension of the pathogenesis is of crucial importance for developing and guiding treatments for the disease. Therefore, we provide an up-to-date consensus on the pathogenesis of non-traumatic ONFH.

Osteonecrosis of the Femoral Head: an Updated Review of ARCO on Pathogenesis, Staging and Treatment.

Non-traumatic osteonecrosis of the femoral head (ONFH) usually affects adults younger than 50 years and frequently leads to femoral head collapse and subsequent arthritis of the hip. It is becoming more prevalent along with increasing use of corticosteroids for the adjuvant therapy of leukemia and other myelogenous diseases as well as management of organ transplantation. This review updated knowledge on the pathogenesis, classification criteria, staging system, and treatment of ONFH.

Diagnosis and Treatment of Femoral Head Osteonecrosis: A Protocol for Development of Evidence-Based Clinical Practice Guidelines.

INTRODUCTION: There are many treatment options for patients who have osteonecrosis of the femoral head (ONFH) and management strategies vary widely both among and within individual countries. Although many researchers have attempted to elucidate the optimal strategies for managing this disease, the lack of large-scale randomized control trials and the lack of agreement on disease staging have curtailed the development of clear-cut guidelines. MATERIALS AND METHODS: The Association Research Circulation Osseous (ARCO) group sought to address three questions for the management of patients who have ONFH: 1) What imaging studies are most sensitive and specific for the diagnostic evaluation of patients who have ONFH?; 2) What is the best treatment strategy for preventing disease progression in patients who have pre-collapse lesions?; and 3) What is the best treatment strategy for patients who have post-collapse disease? The Patient, Intervention, Comparison, and Outcome (PICO) format was used to formulate the search strategy for each research question. A systematic review will be performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. ARCO participants have been allocated to three groups, each representing one of the PICO questions. After qualitative and quantitative analysis of the data extracted from studies pertaining to each of the three research questions, a set of evidence-based clinical practice guidelines will be proposed for the management of patients who have ONFH. DISCUSSION: It is not always clear which treatment method is optimal for the management of ONFH. Thus, many surgeons have developed and performed various procedures based on patient-specific factors. As there is no consensus on the optimal treatment for various stages of disease, it was clear that developing evidence-based clinical practice guidelines would provide more structure and uniformity to management of these patients. Therefore, the results of this systematic review will lead to the development guidelines that may improve patient-care strategies and result in better outcomes for patients who have ONFH.

The 2019 Revised Version of Association Research Circulation Osseous Staging System of Osteonecrosis of the Femoral Head.

BACKGROUND: The Association Research Circulation Osseous (ARCO) presents the 2019 revised staging system of osteonecrosis of the femoral head (ONFH) based on the 1994 ARCO classification. METHODS: In October 2018, ARCO established a task force to revise the staging system of ONFH. The task force involved 29 experts who used a web-based survey for international collaboration. Content validity ratios for each answer were calculated to identify the levels of agreement. For the rating queries, a consensus was defined when more than 70% of the panel members scored a 4 or 5 rating on a 5-point scale. RESULTS: Response rates were 93.1%-100%, and through the 4-round Delphi study, the 1994 ARCO classification for ONFH was successfully revised. The final consensus resulted in the following 4-staged system: stage I-X-ray is normal, but either magnetic resonance imaging or bone scan is positive; stage II-X-ray is abnormal (subtle signs of osteosclerosis, focal osteoporosis, or cystic change in the femoral head) but without any evidence of subchondral fracture, fracture in the necrotic portion, or flattening of the femoral head; stage III-fracture in the subchondral or necrotic zone as seen on X-ray or computed tomography scans. This stage is further divided into stage IIIA (early, femoral head depression ≤2 mm) and stage IIIB (late, femoral head depression >2 mm); and stage IV-X-ray evidence of osteoarthritis with accompanying joint space narrowing, acetabular changes, and/or joint destruction. This revised staging system does not incorporate the previous subclassification or quantitation parameters, but the panels agreed on the future development of a separate grading system for predicting disease progression. CONCLUSION: A staging system has been developed to revise the 1994 ARCO classification for ONFH by an expert panel-based Delphi survey. ARCO approved and recommends this revised system as a universal staging of ONFH.

[Complication analysis after angle-stable CW and OW high tibial osteotomy]. / Komplikationsanalyse nach winkelstabiler CW- und OW-Tibiaumstellungsosteotomie.

BACKGROUND: High tibial osteotomy (HTO) is a good joint-preserving alternative to joint replacement in the treatment of isolated medial varus gonarthrosis. It is, however, accompanied by a number of complications, which can compromise the outcome of the treatment. OBJECTIVES: Analysis and comparison of the complication structure after angle-stable navigated closed wedge (CW) HTO and conventional angle-stable open wedge (OW) HTO, as well as determination of influence factors. MATERIAL AND METHODS: 281 HTO (187 CW- and 94 OWHTO) were analyzed retrospectively. Age, sex, BMI, time of surgery and radiological parameters were included as possible influence factors. A statistical analysis was performed with binary logistic regression. RESULTS: An overall complication rate of 21.4% was revealed (25.1% after CW- and 13.8% after OWHTO, p = 0.02); the major complications occurred after 13.9% CW- and 10.6% OWHTO (p = 0.27); minor complications were observed after 11.2% CW- and 3.2% OWHTO (p = 0.03). This difference results from complications specific to CWHTO (peroneal lesions and pseudarthrosis fibulae). The incidence of pseudarthrosis tibiae was equal in both procedures (7.5%). Age ≥ 52 years and body mass index (BMI) ≥ 30 kg/m2 were the relevant predictors for mechanical complications after CWHTO; these were not relevant for OWHTO. CONCLUSION: The correct patient selection is essential to avoid postoperative complications after HTO. The overall complication rates are lower after OWHTO, mainly through the avoidance of complications typical for CWHTO. OWHTO offers a wider choice with respect to the selection of patients.

Opposite hinge fractures in high tibial osteotomy: a displacement subtype is more critical than a fracture type.

PURPOSE: Analysis of the structure of the fractures of opposite hinge (FOH) after angle-stable closed-wedge (CW) and open-wedge (OW) high tibial osteotomy (HTO), and their influence on the development of tibial pseudarthrosis. METHODS: 187 CW and 94 OWHTOs were analyzed retrospectively. The FOHs in the OWHTO were classified according to Takeuchi, and in the CWHTO-according to the own classification with two types (depending on the direction of FOH). FOHs in both techniques were also subdivided into three subtypes according to displacement (A-non-displaced, B-primarily displaced, C-secondarily displaced). The statistical analysis included correlation analysis and logistic regression. RESULTS: FOHs were found in 81 (43.3%) CW and 39 (41.2%) OWHTOs. The stable type 1 fractures predominated in OWHTO (76.9 vs. 42%, p < 0.001), the unstable type 2 FOHs prevailed in CWHTO (58 vs. 17.9%, p < 0.001). The tibial pseudarthrosis rate was higher with type 1 (20 vs. 12.9%, n.s.) and subtype A (16.7 vs. 6.8%, p = 0.048) FOHs in OWHTO, and with type 2 (20 vs. 0%, p < 0.001) and subtypes B (25 vs. 0%, p < 0.001) and C (29.4 vs. 25%, n.s.) in CWHTO (without FOHs 0.9% in CW and 1.8% in OWHTO, n.s.). Relevant correlations were detected between the pseudarthrosis rate and fracture type only in CWHTO (ρs = 0.298, p < 0.001, OR 24.87 for type 2) and displacement subtype in both groups (for subtype C: ρs = 0.345, p < 0.001, OR 43.75 and ρs = 0.231, p = 0.02, OR 18.0, respectively). CONCLUSIONS: The unstable FOH types were more common in CWHTO. The displacement subtype was more predictive for the development of tibial pseudarthrosis than the fracture type, especially in OWHTO. The secondarily displaced FOHs (subtype C) represented the highest risk for the occurrence of pseudarthrosis in both techniques.

Role of Nrf2 in Fracture Healing: Clinical Aspects of Oxidative Stress.

Fracture healing is a natural process that recapitulates embryonic skeletal development. In the early phase after fracture, reactive oxygen species (ROS) are produced under inflammatory and ischemic conditions due to vessel injury and soft tissue damage, leading to cell death. Usually, such damage during the course of fracture healing can be largely prevented by protective mechanisms and functions of antioxidant enzymes. However, intrinsic oxidative stress can cause excessive toxic radicals, resulting in irreversible damage to cells associated with bone repair during the fracture healing process. Clinically, patients with type-2 diabetes mellitus, osteoporosis, habitual drinkers, or heavy smokers are at risk of impaired fracture healing due to elevated oxidative stress. Although increased levels of oxidative stress markers upon fracture and effects of antioxidants on fracture healing have been reported, a detailed understanding of what causes impaired fracture healing under intrinsic conditions of oxidative stress is lacking. Nuclear factor erythroid 2-related factor 2 (Nrf2) has been identified as a key transcriptional regulator of the expression of antioxidants and detoxifying enzymes. It further not only plays a crucial role in preventing degenerative diseases in multiple organs, but also during fracture healing. This narrative review evaluates the influence of intrinsic oxidative stress on fracture healing and sheds new light on the intriguing role of Nrf2 during bone regeneration in pathological fractures.

Etiologic Classification Criteria of ARCO on Femoral Head Osteonecrosis Part 1: Glucocorticoid-Associated Osteonecrosis.

BACKGROUND: Glucocorticoid usage, a leading cause of osteonecrosis of the femoral head (ONFH), and its prevalence was reported in 25%-50% of non-traumatic ONFH patients. Nevertheless, there have been no unified criteria to classify glucocorticoid-associated ONFH (GA-ONFH). In 2015, the Association Research Circulation Osseous addressed the issue of developing a classification scheme. METHODS: In June 2017, a task force was set up to conduct a Delphi survey concerning ONFH. The task force invited 28 experts in osteonecrosis/bone circulation from 8 countries. Each round of the Delphi survey consists of questionnaires, analysis of replies, and feedback reports to the panel. After 3 rounds of the survey, the panel reached a consensus on the classification criteria. The response rates were 100% (Round 1), 96% (Round 2), and 100% (Round 3), respectively. RESULTS: The consensus on the classification criteria of GA-ONFH included the following: (1) patients should have a history of glucocorticoid use >2 g of prednisolone or its equivalent within a 3-month period; (2) osteonecrosis should be diagnosed within 2 years after glucocorticoid usage, and (3) patients should not have other risk factor(s) besides glucocorticoids. CONCLUSION: Association Research Circulation Osseous established classification criteria to standardize clinical studies concerning GA-ONFH.

Etiologic Classification Criteria of ARCO on Femoral Head Osteonecrosis Part 2: Alcohol-Associated Osteonecrosis.

BACKGROUND: Although alcohol is a leading risk factor for osteonecrosis of the femoral head (ONFH) and its prevalence reportedly ranges from 20% to 45%, there are no unified classification criteria for this subpopulation. In 2015, Association Research Circulation Osseous decided to develop classification criteria for alcohol-associated ONFH. METHODS: In June of 2017, Association Research Circulation Osseous formed a task force to conduct a Delphi survey. The task force invited 28 experts in osteonecrosis/bone circulation from 8 countries. Each round of the Delphi survey included questionnaires, analysis of replies, and feedback reports to the panel. After 3 rounds of the survey, consensus was reached on the classification criteria. The response rates for the 3 Delphi rounds were 100% (round 1), 96% (round 2), and 100% (round 3). RESULTS: The consensus on the classification criteria of alcohol-associated ONFH included the following: (1) patients should have a history of alcohol intake >400 mL/wk (320 g/wk, any type of alcoholic beverage) of pure ethanol for more than 6 months; (2) ONFH should be diagnosed within 1 year after alcohol intake of this dose; and (3) patients should not have other risk factor(s). CONCLUSION: ARCO-established classification criteria to standardize clinical studies concerning AA-ONFH.

Bone-preserving total hip arthroplasty in avascular necrosis of the hip-a matched-pairs analysis.

PURPOSE: Short-stem hip arthroplasty has the potential advantage of femoral bone stock preservation, especially in view of the expected revisions in the often relatively young patients. Despite short-stem hip prosthesis are increasingly used for total hip arthroplasty, there are no sufficient mid- and long-term results especially for patients with avascular femoral head osteonecrosis. The present study investigates mid-term functional results as well as the revision rate following implantation of a short-stem prosthesis. METHODS: In the period 06/2005 until 12/2013, a total of 351 short-stem hip prostheses were implanted. The study included 331 complete data sets. A retrospective analysis was performed using the Oxford Hip Score. All revisions were registered. RESULTS: In a total of 331 prostheses, the Oxford Hip Score was "excellent" in 66.2%, "good" in 12.7%, "fair" in 13.0%, and "poor" in 8.2% with a mean follow-up of 57.4 months (SD ± 29.8; range 24-115). In 26 cases, aseptic osteonecrosis of the hip was the indication (7.9%). The Oxford Hip Score was "excellent" in 66.7%, "good" in 0.0%, "fair" in 20.8%, and "poor" in 12.5%. The cumulated five year survival rate was 96.7%. CONCLUSION: In mid-term observation, the Metha® short-stem prosthesis shows no disadvantage in functional outcome and in survival time compared to a standard hip stem. Providing a correct indication, the Metha® short stem is a valuable option in total hip arthroplasty for younger patients with avascular osteonecrosis of the femoral head. Evaluation has shown no significant differences between aseptic osteonecrosis and other indications.

Pluripotent stem cells escape from senescence-associated DNA methylation changes.

Pluripotent stem cells evade replicative senescence, whereas other primary cells lose their proliferation and differentiation potential after a limited number of cell divisions, and this is accompanied by specific senescence-associated DNA methylation (SA-DNAm) changes. Here, we investigate SA-DNAm changes in mesenchymal stromal cells (MSC) upon long-term culture, irradiation-induced senescence, immortalization, and reprogramming into induced pluripotent stem cells (iPSC) using high-density HumanMethylation450 BeadChips. SA-DNAm changes are highly reproducible and they are enriched in intergenic and nonpromoter regions of developmental genes. Furthermore, SA-hypomethylation in particular appears to be associated with H3K9me3, H3K27me3, and Polycomb-group 2 target genes. We demonstrate that ionizing irradiation, although associated with a senescence phenotype, does not affect SA-DNAm. Furthermore, overexpression of the catalytic subunit of the human telomerase (TERT) or conditional immortalization with a doxycycline-inducible system (TERT and SV40-TAg) result in telomere extension, but do not prevent SA-DNAm. In contrast, we demonstrate that reprogramming into iPSC prevents almost the entire set of SA-DNAm changes. Our results indicate that long-term culture is associated with an epigenetically controlled process that stalls cells in a particular functional state, whereas irradiation-induced senescence and immortalization are not causally related to this process. Absence of SA-DNAm in pluripotent cells may play a central role for their escape from cellular senescence.

Enoxaparin prevents steroid-related avascular necrosis of the femoral head.

Nontraumatic osteonecrosis of the femoral head is still a challenging problem in orthopedic surgery. It is responsible for 10% of the 500,000 hip replacement surgeries in the USA and affects relatively young, active patients in particular. Main reasons for nontraumatic osteonecrosis are glucocorticoid use, alcoholism, thrombophilia, and hypofibrinolysis (Glueck et al., 1997; Orth and Anagnostakos, 2013). One pathomechanism of steroid-induced osteonecrosis is thought to be impaired blood flow to the femoral head caused by increased thrombus formation and vasoconstriction. To investigate the preventive effect of enoxaparin on steroid-related osteonecrosis, we used male New Zealand white rabbits. Osteonecrosis was induced by methylprednisolone-injection (1 × 20 mg/kg body weight). Control animals were treated with phosphate-buffered saline. Treatment consisted of an injection of 11.7 mg/kg body weight of enoxaparin per day (Clexane) in addition to methylprednisolone. Four weeks after methylprednisolone-injection the animals were sacrificed. Histology (hematoxylin-eosin and Ladewig staining) was performed, and empty lacunae and histological signs of osteonecrosis were quantified. Histomorphometry revealed a significant increase in empty lacunae and necrotic changed osteocytes in glucocorticoid-treated animals as compared with the glucocorticoid- and Clexane-treated animals and with the control group. No significant difference was detected between the glucocorticoid and Clexane group and the control group. This finding suggests that cotreatment with enoxaparin has the potential to prevent steroid-associated osteonecrosis.

Knowledge transfer of spinal manipulation skills by student-teachers: a randomised controlled trial.

PURPOSE: To assess the use of peer-assisted learning (PAL) of complex manipulative motor skills with respect to gender in medical students. METHODS: In 2007-2010, 292 students in their 3rd and 4th years of medical school were randomly assigned to two groups [Staff group (SG), PAL group (PG)] led by either staff tutors or student-teachers (ST). The students were taught bimanual practical and diagnostic skills (course education module of eight separate lessons) as well as a general introduction to the theory of spinal manipulative therapy. In addition to qualitative data collection (Likert scale), evaluation was performed using a multiple-choice questionnaire in addition to an objective structured clinical examination (OSCE). RESULTS: Complex motor skills as well as palpatory diagnostic competencies could in fact be better taught through professionals than through ST (manipulative OSCE grades/diagnostic OSCE score; SG vs. PG; male: P = 0.017/P < 0.001, female: P < 0.001/P < 0.001). The registration of theoretical knowledge showed equal results in students taught by staff or ST. In both teaching groups (SG: n = 147, PG: n = 145), no significant differences were observed between male and female students in matters of manipulative skills or theoretical knowledge. Diagnostic competencies were better in females than in males in the staff group (P = 0.041) Overall, students were more satisfied with the environment provided by professional teachers than by ST, though male students regarded the PAL system more suspiciously than their female counterparts. CONCLUSIONS: The peer-assisted learning system does not seem to be generally qualified to transfer such complex spatiotemporal demands as spinal manipulative procedures.

Is helical blade nailing superior to locked minimally invasive plating in unstable pertrochanteric fractures?

BACKGROUND: Technical advancements have produced many challenges to intramedullary implants for unstable pertrochanteric fractures. Helical blade fixation of the femoral head has the theoretical advantages of higher rotational stability and cutout resistance and should have a lower rate of reoperation than a locked plating technique. QUESTIONS/PURPOSES: We asked whether (1) helical blade nailing reduces the rate of reoperation within 24 months compared with locked plating and (2) any of various preoperative, intraoperative, or postoperative factors predicted failure in these two groups. METHODS: We prospectively enrolled 108 patients with unstable pertrochanteric fractures in a surgeon-allocated study between November 2005 and November 2008: 54 with percutaneous compression plates (PCCP) and 54 with proximal femoral nail antirotation (PFNA). We evaluated patients regarding reoperation, mortality, and function. Seventy-four patients had a minimum followup of 24 months (mean, 26 months; range, 24-30 months). RESULTS: We found no differences in the number of reoperations attributable to mechanical problems in the two groups: PCCP = six and PFNA = five. Despite a greater incidence of postoperative lateral wall fractures with helical blade nailing, only postoperative varisation of the neck-shaft angle and tip-apex distance (33 mm versus 28 mm) predicted reoperation. Mortality and function were similar in the two groups. CONCLUSIONS: Our data suggest unstable pertrochanteric fractures may be fixed either with locked extramedullary small-diameter screw systems to avoid lateral wall fractures or with the new intramedullary systems to avoid potential mechanical complications of a broken lateral wall. Tip-apex distance and preservation of the preoperative femoral neck-shaft angle are the key technical factors for prevention of reoperation. LEVEL OF EVIDENCE: Level III, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.

Marginal contribution of UKS- versus TKA in varus arthritis of the knee.

BACKGROUND: In recent years, decisions regarding the treatment of individual patients have increasingly been affected by economic considerations. The G-DRG system reimburses sledge endoprosthetic implantations at a much lower rate than surface replacements and at significantly different cost weights (CW). Therefore, when only G-DRG payments are considered, TKA produces higher gains. Taking only these revenues alone into consideration, however, does not provide the basis of an economically sound decision-making process. The target of this research was to present a comparison between variable costs of the two procedures. METHODS: The mean cost and performance data of 28 Endo-Modell (Link company) sledge implantations (UKS) and of 85 NexGen CR surface replacement total knee arthroplasties (TKA; Zimmer company) were compared in 2007. RESULTS: From the perspective of the hospital, UKS treatment is of greater economic advantage when the medical indication is given. In preferring UKS marginal contribution can be improved, and although the relative weighting is comparatively low, the costs are significantly lower than in a comparative analysis of TKA. Based on the length of stay required for each procedure the average daily CW for UKS can be calculated as 0.1728, while being 0.1955 for TKA. The earlier release of the first patient results in another patient being admitted 1.5 days earlier and thus an increase in case mix. Meanwhile, the case-mix index and the costs of care per case decrease ceteris paribus. CONCLUSION: Assuming the correct medical indication, the hospital seeking to maximize its marginal contribution would be wise to select sledge endoprosthesis implantation. Considering the economic perspective of gains and costs, the assumption that TKA is advantageous could not be confirmed in the present study.

The key-muscle concept: a long-term low-dose injection strategy for botulinum toxin A treatment in cerebral palsy.

Botulinum toxin (BoNT) is a well established treatment in cerebral palsy. A uniform dose strategy is, however, missing. We reviewed 35 children with spastic cerebral palsy treated with BoNT according to a newly-developed Key-Muscle concept. All patients received at least 4 BoNT treatments. Systemic side effects or secondary non-response were not observed. After a mean follow-up of 303 months, none of these patients needed bone surgery whereas 6 underwent soft tissue procedures. The Key-Muscle concept is a safe and effective treatment in spastic cerebral palsy. It respects the need for long-term therapy during motor development. Contractures and lever arm disease can be avoided.

Adverse Effects of Oxidative Stress on Bone and Vasculature in Corticosteroid-Associated Osteonecrosis: Potential Role of Nuclear Factor Erythroid 2-Related Factor 2 in Cytoprotection.

Significance: Osteonecrosis (ON) is characterized by bone tissue death due to disturbance of the nutrient artery. The detailed process leading to the necrotic changes has not been fully elucidated. Clinically, high-dose corticosteroid therapy is one of the main culprits behind osteonecrosis of the femoral head (ONFH). Recent Advances: Numerous studies have proposed that such ischemia concerns various intravascular mechanisms. Of all reported risk factors, the involvement of oxidative stress in the irreversible damage suffered by bone-related and vascular endothelial cells during ischemia simply cannot be overlooked. Several articles also have sought to elucidate oxidative stress in relation to ON using animal models or in vitro cell cultures. Critical Issues: However, as far as we know, antioxidant monotherapy has still not succeeded in preventing ONFH in humans. To provide this desideratum, we herein summarize the current knowledge about the influence of oxidative stress on ON, together with data about the preventive effects of administering antioxidants in corticosteroid-induced ON animal models. Moreover, oxidative stress is counteracted by nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent cytoprotective network through regulating antioxidant expressions. Therefore, we also describe Nrf2 regulation and highlight its role in the pathology of ON. Future Directions: This is a review of all available literature to date aimed at developing a deeper understanding of the pathological mechanism behind ON from the perspective of oxidative stress. It may be hoped that this synthesis will spark the development of a prophylactic strategy to benefit corticosteroid-associated ONFH patients. Antioxid. Redox Signal. 35, 357-376.

Impact of individual platelet lysates on isolation and growth of human mesenchymal stromal cells.

BACKGROUND AIMS: Culture medium for mesenchymal stromal cells (MSC) is frequently supplemented with fetal calf serum (FCS). FCS can induce xenogeneic immune reactions, transmit bovine pathogens and has a high lot-to-lot variability that hampers reproducibility of results. Several studies have demonstrated that pooled human platelet lysate (HPL) provides an attractive alternative for FCS. However, little is known about the variation between different platelet lysates. METHODS: We compared activities of individual HPL on initial fibroblastoid colony-forming units (CFU-F), proliferation, in vitro differentiation and long-term culture. These data were correlated with chemokine profiles of HPL. RESULTS: Isolation of MSC with either HPL or FCS resulted in similar CFU-F frequency, colony morphology, immunophenotype and adipogenic differentiation potential. Osteogenic differentiation was even more pronounced in HPL than FCS. There were significant differences in MSC proliferation with different HPL, but it was always higher in comparison with FCS. Cell growth correlated with the concentration of platelet-derived growth factor (PDGF) and there was a moderate association with platelet counts. All HPL facilitated expansion for more than 20 population doublings. CONCLUSIONS: Taken together, reliable long-term expansion was possible with all HPL, although there was some variation in platelet lysates of individual units. Therefore the use of donor recipient-matched or autologous HPL is feasible for therapeutic MSC products.