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The potential use of bone marrow mesenchymal stromal cells (BM-MSCs) for the treatment of osteonecrosis in sickle cell disease (SCD) patients is increasing. However, convenient BM-MSC quantification and functional property assays are critical factors for cell-based therapies yet to be optimized. This study was designed to quantify the MSC population in bone marrow (BM) samples from SCD patients with osteonecrosis (SCD group) and patients with osteoarticular complications not related to SCD (NS group), using flow cytometry for CD271 + CD45 -/low cell phenotype and CFU-F assay. We also compared expanded BM-MSC osteogenic differentiation, migration, and cytokine secretion potential between these groups. The mean total cell number, CFU-F count, and CD271 + CD45 -/low cells in BM mononuclear concentrate were significantly higher in SCD than in NS patients. A significant correlation between CD271 + CD45 -/low cell number and CFU-F counts was found in SCD ( r = 0.7483; p = 0.0070) and NS ( r = 0.7167; p = 0.0370) BM concentrates. An age-related quantitative reduction of CFU-F counts and CD271 + CD45 -/low cell number was noted. Furthermore, no significant differences in the morphology, replicative capacity, expression of surface markers, multidifferentiation potential, and secretion of cytokines were found in expanded BM-MSCs from SCD and NS groups after in vitro culturing. Collectively, this work provides important data for the suitable measurement and expansion of BM-MSC in support to advanced cell-based therapies for SCD patients with osteonecrosis., Competing Interests: The authors declare no conflict of interest with respect to the authorship, research, and/or publication of this article., (Copyright © 2020 Tiago O. Ribeiro et al.)

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Purpose: The aim of this study was to describe the clinical features of osteonecrosis (ON) in sickle cell disease (SCD) patients in Bahia, a Northeast state with the highest prevalence of the disease in Brazil., Methods: Between 2006 and 2017, 283 cases of osteonecrosis in SCD patients were enrolled to analyse the age at diagnosis, genotype, gender, pain, distribution of the lesions and disease staging. MRI and radiograph were obtained at the participation., Results: Of the 283 SCD cases, 120 (42.4%) were haemoglobin SS genotype while 163 (57.6%) were SC genotype. Two hundred and forty-six cases were bilateral and 37 were unilateral, with an average age at diagnosis of 33.7 (range 10-67) years. The most frequent identified ON site not only was the hip (74.6%), but also affected shoulder, knee and ankle. Most cases presented at early stage I (172, 60.8%) disease. No significant differences on the features of osteonecrosis were identified between haemoglobin SS and haemoglobin SC cases., Conclusions: Given the relatively high prevalence of bilateral osteonecrosis at early stages, painful symptoms and rather late age at diagnosis, SCD patients should have radiological examination of their joints more often in order to prevent severe functional disability and increase patient's life quality.

Background: The purpose of our study was to evaluate safety, feasibility and clinical results of bone marrow mononuclear cell (BMC) implantation for early-stage osteonecrosis of the knee (OK) secondary to sickle cell disease., Methods: Thirty-three SCD patients (45 knees) with OK treated with BMC implantation in the osteonecrotic lesion were clinically and functionally evaluated through the American Knee Society Clinical Score (KSS), Knee Functional Score (KFS) and Numeric Rating Scale (NRS) pain score. MRI and radiographic examinations of the knee were assessed during a period of five years after intervention., Results: No complications or serious adverse event were associated with BMC implantation. From preoperative assessment to the latest follow-up, there was a significant (p < 0.001) improvement of clinical KSS (64.3 ± 9.7, range: 45-80 and 2.2 ± 4.1, range: 84-100, respectively), KFS (44.5 ± 8.0, range: 30-55 and 91.6 ± 5.8, range: 80-100, respectively) and reduction of NRS pain score (6.7 ± 1.2, range: 4-9 and 3.4 ± 1.0, range: 2-5, respectively). In total, 87% of patients (29/33) consistently experienced improvements in joint function and activity level as compared to preoperative score. No patient had additional surgery following BMC implantation. Radiographic assessment showed joint preservation and no progression to subchondral collapse at most recent follow-up., Conclusions: The technique of BMC implantation is a promising, relatively simple and safe procedure for OK in SCD patients. Larger and long-term controlled trials are needed to support its clinical effectiveness., Trial Registration: ClinicalTrials.gov NCT02448121 . Retrospectively registered 19 May 2015.

Chronic pain in Sickle Cell Disease (SCD) is probably related to maladaptive plasticity of brain areas involved in nociceptive processing. Transcranial Direct Current Stimulation (tDCS) and Peripheral Electrical Stimulation (PES) can modulate cortical excitability and help to control chronic pain. Studies have shown that combined use of tDCS and PES has additive effects. However, to date, no study investigated additive effects of these neuromodulatory techniques on chronic pain in patients with SCD. This protocol describes a study aiming to assess whether combined use of tDCS and PES more effectively alleviate pain in patients with SCD compared to single use of each technique. The study consists of a one-session double blind, block-randomized clinical trial (NCT02813629) in which 128 participants with SCD and femoral osteonecrosis will be enrolled. Stepwise procedures will occur on two independent days. On day 1, participants will be screened for eligibility criteria. On day 2, data collection will occur in four stages: sample characterization, baseline assessment, intervention, and post-intervention assessment. These procedures will last ~5 h. Participants will be divided into two groups according to homozygous for S allele (HbSS) ( n = 64) and heterozygous for S and C alleles (HbSC) ( n = 64) genotypes. Participants in each group will be randomly assigned, equally, to one of the following interventions: (1) active tDCS + active PES; (2) active tDCS + sham PES; (3) sham tDCS + active PES; and (4) sham tDCS + sham PES. Active tDCS intervention will consist of 20 min 2 mA anodic stimulation over the primary motor cortex contralateral to the most painful hip. Active PES intervention will consist of 30 min sensory electrical stimulation at 100 Hz over the most painful hip. The main study outcome will be pain intensity, measured by a Visual Analogue Scale. In addition, electroencephalographic power density, cortical maps of the gluteus maximus muscle elicited by Transcranial Magnetic Stimulation (TMS), serum levels of Brain-derived Neurotrophic Factor (BDNF), and Tumor Necrosis Factor (TNF) will be assessed as secondary outcomes. Data will be analyzed using ANOVA of repeated measures, controlling for confounding variables.

Recurrent chronic leg ulcers are among the most severe vasculopathic complications of sickle cell disease (SCD). Their treatment remains a challenge. Stem cell therapy with bone marrow mononuclear cells (BMMC) is a promising new therapeutic option for other forms of chronic ulcers. This prospective pilot study was performed to evaluate safety and feasibility of BMMC implantation in patients with SCD and chronic leg ulcers (SCLU). Ulcer closure, recurrence and local pain were evaluated. BMMC were successfully administered to 23 SCLU patients and no serious adverse events occurred. During the 6-month follow-up period, 91·3% of patients had improved ulcer pain compared with baseline and 29·2% of the treated ulcers achieved total healing. The frequency of progenitor stem cells (CD34CD45 low and fibroblast colony-forming units) in BMMC was found to be significantly reduced in SCLU patients and compared to SCD patients without ulcers (P < 0·004 and P < 0·01, respectively). No relationship was observed between treatment outcome and the number of implanted BM progenitor stem cells. In conclusion, BMMC implantation is a feasible and safe procedure, showing favourable outcomes for the treatment of SCLU, and encouraging further controlled clinical trials., (© 2016 John Wiley & Sons Ltd.)

Background: Little is known about the rate of, and factors affecting, progression of talar osteonecrosis related to sickle cell disease. Adult patients with sickle cell disease who presented with hip osteonecrosis were evaluated for talar osteonecrosis with radiographs and magnetic resonance imaging (MRI). Forty-five of them (75 tali) were diagnosed with talar osteonecrosis, and this group was evaluated for factors influencing the progression of the disease., Methods: Forty-five patients with sickle cell disease and osteonecrosis of the talus were identified with radiographs and MRI between 1985 and 1995. Seven of these patients were homozygous for hemoglobin S (S/S genotype), 26 had hemoglobin S/hemoglobin C, and 12 had hemoglobin S/beta-thalassemia. The talar osteonecrosis was graded with radiographs and MRI. The patients were followed with clinical examination and radiographs every 6 months until talar collapse and every year after the collapse., Results: The osteonecrosis was unilateral in 15 patients and bilateral in 30 at the time of the initial examination. Forty-five ankles were asymptomatic and 30 were symptomatic at the initial evaluation. MRI performed at the time of the most recent follow-up, and compared with MRI performed at diagnosis, did not show partial or total regression of the osteonecrosis in any of the patients, even those with asymptomatic stage-I osteonecrosis. At the time of the most recent follow-up (mean, 20 years; range, 15 to 25 years), pain and collapse had developed in all except 12 ankles. The stage of the osteonecrosis at the initial visit, pain, the genotype of the sickle cell disease, and the extent and location of the lesion in the talus were risk factors for progression of the disease., Conclusions: In the majority of the patients with sickle cell disease, osteonecrosis of the talus should be expected to show relevant clinical and radiographic evidence of progression over a long period., Level of Evidence: Prospective Level II. See Instructions for Authors for a complete description of levels of evidence., (Copyright © 2016 by The Journal of Bone and Joint Surgery, Incorporated.)

Introduction: Stem cell therapy with bone marrow-derived mononuclear cells (BMMCs) is an option for improving joint function in osteonecrosis of the femoral head (ONFH). Bone marrow-derived mesenchymal stromal cell (MSC) numbers and their osteogenic differentiation are decreased in patients with ONFH. However, whether this decrease also extends to the early stages of ONFH in sickle cell disease (SCD) is still unclear., Methods: We conducted a phase I/II, non-controlled study to determine efficacy and safety of BMMC implantation using a minimally invasive technique in SCD patients with ONFH. Eighty-nine patients were recruited and followed up for 60 months after surgery. Clinical and radiographic findings were assessed, and data were completed by in vitro analysis., Results: At the final follow-up (60 months) there was a significant improvement in clinical joint symptoms and pain relief as measured by the Harris Hip Score (P = 0.0005). In addition, after the BMMC implantation procedure, radiographic assessment showed disease stabilization and only 3.7 % of the treated patients did not achieve a satisfactory clinical result. The amount of fibroblast colony-forming units was 28.2 ± 13.9 per 1 million BMMCs after concentration. Flow cytometry analysis showed a significantly higher number of hematopoietic stem/endothelial progenitor cell markers in concentrated BMMCs when compared with bone marrow aspirate, indicating an enrichment of these cell types. Isolated MSCs from SCD patients with pre-collapse ONFH maintained the replicative capacity without significant loss of their specific biomolecular characteristics, multi-differentiation potential, and osteogenic differentiation activities. Cytokines and growth factors (interleukin-8, transforming growth factor-beta, stromal cell-derived factor-1alpha and vascular endothelial growth factor) that mediate endogenous bone regeneration were also produced by expanded MSCs from SCD patients., Conclusion: The autologous BMMC implantation with a minimally invasive technique resulted in significant pain relief and halted the progression of early stages of ONFH in SCD patients. MSCs from SCD patients display biological properties that may add to the efficiency of surgical treatment in ONFH. In summary, our results indicate that infusion of BMMCs enriched with stem/progenitor cells is a safe and effective treatment for the early stages of ONFH in SCD patients., Trial Registration: ClinicalTrials.gov NCT02448121; registered 15 May 2015.

Background: Septic arthritis is a known complication of sickle cell disease (SCD) in children, and the association with osteomyelitis and osteonecrosis has been described. However, it is unclear whether this association applies to adults., Questions/purposes: We therefore asked whether septic arthritis is a frequent complication in adults with SCD and whether it also is associated with osteomyelitis or osteonecrosis., Methods: We retrospectively reviewed the charts of 2000 consecutive adult patients diagnosed with SCD and recorded symptoms, select findings during physical examination, laboratory data, and select radiographic CT, and MRI observations., Results: Fifty-nine of the 2000 patients (3%) had septic arthritis, 56 of the 59 patients had hemoglobin SS. Thirty-six of the 59 infections (61%) were in the hip. The most frequent findings were pain, swelling, fever greater than 38.2 degrees C (71% of cases), a leukocyte count exceeding 15,000/mm(3) (range, 7900-32,300/mm(3)), a Westergren sedimentation rate greater than 24 mm/hour, and C-reactive protein exceeding 20 mg/L. Cultures were positive in 96% of the joint aspirates. Staphylococcus and Gram-negative infection predominated; no patients had Salmonella joint infections. Preexisting factors of bacterial arthritis included osteonecrosis (29 patients) and osteomyelitis (37 cases) in childhood. Diabetes, rheumatoid arthritis, glucocorticoids, and immunoparesis related to medical treatment by hydroxyurea were associated comorbidities. CT and MRI confirmed the diagnosis of associated osteonecrosis or osteomyelitis and allowed joint aspiration and detection of soft tissue abscess., Conclusions: The incidence of septic arthritis in adults with SCD is low, but often is associated with osteomyelitis or osteonecrosis., Level of Evidence: Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence.

The aim of this review paper is to define the fixation of the cemented stem. Polymethyl methacrylate, otherwise known as "bone cement", has been used in the fixation of hip implants since the early 1960s. Sir John Charnley, the pioneer of modern hip replacement, incorporated the use of cement in the development of low frictional torque hip arthroplasty. In this paper, the concepts of femoral stem design and fixation, clinical results, and advances in understanding of the optimal use of cement are reviewed. The purpose of this paper is to help understanding and discussions on the thickness and the porosity of the cement mantle in total hip arthroplasty. Cement does not act as an adhesive, as sometimes thought, but relies on an interlocking fit to provide mechanical stability at the cement-bone interface, while at the prosthesis- cement interface it achieves stability by optimizing the fit of the implant in the cement mantle, such as in a tapered femoral stem.