Is the High Healing Index a Complication of Progressive Long Bone Lengthening? Observations from a Cohort of 178 Children Treated with Circular External Fixation for Lower Limb Length Discrepancy.

The use of external fixators (EFs) for lower limb lengthening is common for treating lower limb length discrepancy (LLD) in children. The concern at present revolves around extended treatment times, with some suggesting a healing index (HI) > 45 days/cm as a major complication. The aim of this study is to assess the factors affecting bone healing and treatment duration in children who undergo limb lengthening for LLD using circular EFs. A total of 240 lengthening procedures on 178 children affected by congenital or acquired LLDs (mean age at surgery 13.8 ± 2.8 years) were retrospectively evaluated. Complications according to Lascombes' classification and treatment duration factors were analyzed. Mean HI was 57 ± 25 days/cm for the femur and 55 ± 24 days/cm for the tibia, with an HI > 45 days/cm in 64% of the procedures. A total of 189 procedures (79%) reported complications; 85 had an HI > 45 days/cm as the sole complication. While reducing the frame time is crucial, revising the classifications is necessary to avoid the overestimation of complications.

Good Subjective Outcomes, Stable Knee and High Return to Sport after Tibial Eminence Avulsion Fracture in Children.

Avulsion fracture of the tibial spine (TSA) is uncommon in children, although its incidence is increasing with the earlier practice of competitive sport activities. This study aims to report mid to long term outcomes in children who sustained a TSA, with a special focus on a return to sport activities. Skeletally immature patients with a TSA, treated in two orthopedic hospitals, were evaluated for range of motion and knee laxity using KT1000, KiRA and Rolimeter. The pediatric International Knee Documentation Committee score (Pedi-IKDC) and the Hospital for Special Surgery pediatric Functional Activity Brief Scale (Pedi-FABS) questionnaires were recorded during the latest visit. Forty-two children were included. Twenty-six were treated nonoperatively and 16 underwent surgery. At a mean follow-up of 6.9 ± 3.6 years, 36 patients completed the questionnaires and 23 patients were tested with arthrometers. Among them, 96% had normal knee laxity. The Pedi-IKDC score averaged 96.4 ± 5.7 points, while the mean Pedi-FABS was 22.2 ± 5.9 points, without statistically significant differences between groups. Twenty-eight patients (78%) returned to their previous level of sport activity (eight amateur, 13 competitive, seven elite athletes). Eight patients (22%) quit sport, mostly because of re-injury fear. If properly treated, pediatric TSAs achieve a high rate of successful healing, with complete restoration of knee stability and an early return to sport activities.

Operative versus nonoperative treatment in children with painful rigid flatfoot and talocalcaneal coalition.

BACKGROUND: The management of painful rigid flatfoot (RFF) with talocalcaneal coalition (TCC) is controversial. We aimed to compare operative and nonoperative treatment in children with RFF and TCC. METHODS: We retrospectively reviewed medical records and radiographs of children with RFF and TTC treated between 2005 and 2015. The nonoperative treatment consisted of manipulation under anesthesia, cast immobilization and shoe insert after cast removal. The operative treatment consisted of combined TCC resection, graft interposition and subtalar arthroereisis. RESULTS: Thirty-four children (47 ft) in the nonoperative group and twenty-one children (34 ft) in the operative group were included. No differences were found between groups, concerning baseline characteristics. The mean age at treatment was 11.8 years (9-17): 11.6 (9-17) for the nonoperative group, 12.2 (10-15) for the operative group. The mean follow-up averaged 6.6 (3-12) years and was significantly longer in the nonoperative group (7.8 versus 4.7 years; p < 0.0005), since the operative procedure was increasingly practiced in the latest years. There were no complications in either groups, but 6 patients (7 ft) in the nonoperative group were unsatisfied and required surgery. At the latest follow-up, the AOFAS-AHS improved in both groups, although the operative group showed significantly better improvement. The operative group reported also significantly better FADI score, after adjustment for follow-up and baseline variables. CONCLUSION: The operative treatment showed better results compared to the nonoperative treatment. Symptomatic RFF with TCC in children can be effectively treated in one step with resection, graft interposition and subtalar arthroereisis. Further prospective randomized studies are needed to confirm our findings and to identify the best operative strategy in this condition.

Synthesis and colloidal characterization of folic acid-modified PEG-b-PCL Micelles for methotrexate delivery.

Hydrophobic drugs, such as methotrexate, are not easily delivered into the human body. Therefore, the use of amphiphilic nanoplatforms to the transport of these drugs through the bloodstream is a challenge. While the hydrophobic region interacts with the drug, the hydrophilic outer layer enhances its bioavailability and circulation time. Poly (ethylene glycol)-block-poly(ε-caprolactone) PEG-b-PCL micelles are biodegradable and biocompatible, allowing its use as a nanocarrier for drug delivery systems. The stealth property of PEG that composes the outer layer of nanoplatforms, makes the micelle unperceivable to phagocytic cells, increasing the circulation time in the human body. In addition, folic acid functionalization enables micelle selectively targeting to cancer cells, improving treatment efficiency and reducing side effects. In this work, PEG-b-PCL copolymer was synthesized by ring opening polymerization (ROP) of the ε-caprolactone with Poly(ethylene glycol) as a macroinitiator and tin(II) 2-ethyl hexanoate as a catalyst. Functionalization of such micelles with folic acid occurred through the modification of the PEG terminal group. The surface modification of the copolymer micelles resulted in higher critical micellar concentration (CMC), increasing approximately 100 times. The synthesis of the copolymers resulted in molecular weight around 3000 g mol-1 with low polydispersity. The polymer micelles have a hydrodynamic diameter in the range of 100-200 nm and the functionalized sample doesn't show aggregation in the considered pH range. High incorporation efficiency was obtained with a minimum percentage of 85%. The drug release profile and linearization from the Peppas model confirmed the interaction of methotrexate with the hydrophobic segment of the copolymer and its release mechanism by relaxation and/or degradation of the chains, making PEG-b-PCL micelles suitable candidates for hydrophobic drug delivery systems.

Alginate-Based Delivery Systems for Bevacizumab Local Therapy: In Vitro Structural Features and Release Properties.

Alginate-based polyelectrolyte complexes (PECs) and hydrogel were engineered as platforms for local bevacizumab (BVZ) therapy. This study provides deep comprehension on the microstructures of such systems, and their correlation with drug-release patterns. PECs and hydrogel were characterized using Fourier transform infrared spectroscopy, small-angle X-ray scattering, scanning electron microscopy, atomic force microscopy, and porosimetry. Structural investigations indicated that PECs are formed by supramolecular interactions, resulting in physically cross-linked polymer networks, whereas the BVZ-loaded hydrogel has a more compact and rigid structure, promoting better entrapment of BVZ. PECs and hydrogel were able to control the BVZ release for 4 and 8 days, respectively. Their release profiles correlated best with the Higuchi and Korsmeyer-Peppas models, respectively, indicating drug diffusion as the limiting step for drug release. Furthermore, BVZ remained biologically active in vitro after its incorporation into the hydrogel system. Together, these studies confirm that PECs and hydrogel exhibit different porous structures and physicochemical properties, making them promising platforms that allow the modulation of BVZ release meeting different requirements.

The Critical Role of Thioacetamide Concentration in the Formation of ZnO/ZnS Heterostructures by Sol-Gel Process.

ZnO/ZnS heterostructures have emerged as an attractive approach for tailoring the properties of particles comprising these semiconductors. They can be synthesized using low temperature sol-gel routes. The present work yields insight into the mechanisms involved in the formation of ZnO/ZnS nanostructures. ZnO colloidal suspensions, prepared by hydrolysis and condensation of a Zn acetate precursor solution, were allowed to react with an ethanolic thioacetamide solution (TAA) as sulfur source. The reactions were monitored in situ by Small Angle X-ray Scattering (SAXS) and UV-vis spectroscopy, and the final colloidal suspensions were characterized by High Resolution Transmission Electron Microscopy (HRTEM). The powders extracted at the end of the reactions were analyzed by X-ray Absorption spectroscopy (XAS) and X-ray diffraction (XRD). Depending on TAA concentration, different nanostructures were revealed. ZnO and ZnS phases were mainly obtained at low and high TAA concentrations, respectively. At intermediate TAA concentrations, we evidenced the formation of ZnO/ZnS heterostructures. ZnS formation could take place via direct crystal growth involving Zn ions remaining in solution and S ions provided by TAA and/or chemical conversion of ZnO to ZnS. The combination of all the characterization techniques was crucial to elucidate the reaction steps and the nature of the final products.

Refixation, allograft and adjuvant cell therapy to treat nonunion of the femoral neck in a child.

INTRODUCTION: Idiopathic posttraumatic nonunion is a rare condition in children; the treatment of this complication is still controversial in this peculiar population. CASE REPORT: We report a case of a subcapital type II femoral neck fracture, in a 12-year-old boy, which was initially treated by internal fixation and subsequently went on to a nonunion at the femoral neck, in absence of infection or other disease.1 year after index surgery we performed surgical debridement and refixation with plate and bone allograft, added with autologous bone marrow aspiration concentrate (BMAC) and platelet-rich fibrin (PRF).After 3 months the nonunion healed and the boy was allowed full weight-bearing. CONCLUSIONS: Combined surgery and adjuvant cell therapy can be considered an option of treatment in nonunion of the femoral neck in the paediatric population.

New insights into osteogenic and chondrogenic differentiation of human bone marrow mesenchymal stem cells and their potential clinical applications for bone regeneration in pediatric orthopaedics.

Human mesenchymal stem cells (hMSCs) are pluripotent adult stem cells capable of being differentiated into osteoblasts, adipocytes, and chondrocytes. The osteogenic differentiation of hMSCs is regulated either by systemic hormones or by local growth factors able to induce specific intracellular signal pathways that modify the expression and activity of several transcription factors. Runt-related transcription factor 2 (Runx2) and Wnt signaling-related molecules are the major factors critically involved in the osteogenic differentiation process by hMSCs, and SRY-related high-mobility-group (HMG) box transcription factor 9 (SOX9) is involved in the chondrogenic one. hMSCs have generated a great interest in the field of regenerative medicine, particularly in bone regeneration. In this paper, we focused our attention on the molecular mechanisms involved in osteogenic and chondrogenic differentiation of hMSC, and the potential clinical use of hMSCs in osteoarticular pediatric disease characterized by fracture nonunion and pseudarthrosis.

Serum levels of fibroblast growth factor 2 in children with orthopedic diseases: potential role in predicting bone healing.

Fibroblast growth factor 2 (FGF-2) plays an important role in the early phases of bone healing. In this study, we measured FGF-2 serum levels in 88 children undergoing surgical treatment for congenital (n = 49) or acquired (n = 39) orthopedic conditions, which were associated (n = 35) or not (n = 53) with bone lesions, to assess whether serum levels of FGF-2 varied according to the underlying disease and may predict clinical outcomes. FGF-2 serum levels were significantly lower in patients who did not heal after surgery (p = 0.008). Diagnostic accuracy was validated statistically, and the ROC curve provided a threshold value useful in discriminating good versus poor outcomes. The relationship between FGF-2 and bone healing was supported by in vitro experiments. A mineralization assay was performed on bone marrow stromal cells from three patients with congenital pseudarthrosis, who had low serum levels of FGF-2 and a poor clinical outcome after surgical treatment. Autologous serum alone was not sufficient to induce in vitro mineralization, but it did occur when cells were cultured with different sources of exogenous growth factors (GFs), including recombinant FGF-2 and homologous serum collected from children with fractures, high FGF-2 levels, and a good clinical outcome. In conclusion, our findings suggest that osteoinductive GFs are essential for bone repair, and that the amount of circulating FGF-2 may predict bone healing.

A regenerative approach for bone repair in congenital pseudarthrosis of the tibia associated or not associated with type 1 neurofibromatosis: correlation between laboratory findings and clinical outcome.

BACKGROUND AND AIMS: Congenital pseudarthrosis of the tibia (CPT) is a rare orthopedic disease presenting spontaneous fractures that do not heal. The treatment of CPT is characterized by repeated surgical procedures that often fail, with the inevitable outcome of severe disability and amputation. We tested the hypothesis that CPT may benefit from regenerative strategies based on mesenchymal stromal cells (MSC) combined with platelet-rich fibrin (PRF) as a source of growth factors. The aim of the study was to verify whether laboratory testing to assess the osteogenic properties of MSC and the osteo-inductive activity of PRF correlated with the clinical outcome. METHODS: Ten patients affected by refractory CPT were treated by using MSC derived from the iliac crest (IC-MSC), PRF and lyophilized bone. In six patients, CPT was associated with type 1 neurofibromatosis (NF1). Biochemical, functional and molecular assays were performed to assess the intrinsic osteogenic potential of IC-MSC (cells cultured with fetal calf serum) and the osteo-inductive properties of PRF (cells cultured with autologous serum). RESULTS: Bone consolidation was obtained in three patients who had CPT and NF1. In these patients, the IC-MSC exposed to autologous serum were able to form mineral nodules in vitro, while the mineralizing ability was totally abrogated in patients with a poor clinical outcome. CONCLUSIONS: Cell therapy may be a useful tool for the treatment of refractory CPT because it increases the opportunity to achieve effective bone tissue regeneration. Our data suggest that the presence of pro-osteogenic growth factors is an essential requirement for bone healing.

Biological basis for the use of autologous bone marrow stromal cells in the treatment of congenital pseudarthrosis of the tibia.

The study was designed to establish the biological basis for the use of autologous bone-marrow stromal cells (MSC) in order to improve the curing opportunities of congenital pseudarthrosis of the tibia (CPT). The investigation was planned by taking into account that the pathophysiology of bone healing mainly depends on the osteogenic potential of the resident cells, although several factors play a crucial role in restoring the normal bone structure. Bone marrow samples were collected from the lesion site (P) and the iliac crest (IC) of 7 patients affected by CPT and type 1 neurofibromatosis (NF1+) and 6 patients affected by CPT without NF1 (NF1-). Four patients without CPT served as control group. Biochemical, functional and molecular assays showed that the ability to generate bone-forming cells was higher in IC-MSC than in P-MSC, but lower in CPT patients than in control group. We evaluated whether host factors, such as autologous serum and the microenvironment surrounding the pseudarthrosis lesion, could impair the osteogenic differentiation of IC-MSC. Autologous serum was less effective than FBS in promoting the IC-MSC differentiation, but the damage was more evident in NF1- than in NF1+ patients. Additionally, the supernatant of osteoblast cultures obtained from bone fragments close to the lesion site favoured the differentiation of IC-MSC in NF1- patients. In summary, our results suggest that MSC transplantation could be a promising strategy for the therapy of CPT. Further studies are warranted to confirm the clinical effectiveness in comparison to standard surgical treatment.

Microscopia de força atômica no estudo da superfície endotelial de bifurcações arteriais cerebrais humanas / Atomic force microscopy in the study of the endothelial surface of the human brain artery bifurcations

Objetivo: Apresentar o estudo morfológico do endotélio vascular de artérias cerebrais humanas e discutir aplicações e limitações da miceoscopia de força atômica (AFM) no estudo de patologia vascular. Material e método: Foram utilizadas amostras do segmento M1 e da bifurcação da artéria cerebral média, com e sem doença aterosclerótica. Imagens topográficas, obtidas por microscopia eletrônica de varredura (MEV) das amostras fixadas quimicamente e desidratadas mediante ponto crítico foram confrontadas com imagens de amostras não fixadas, obtidas por AFM. Resultados: As células endoteliais nos segmentos retos de M1 e da bifurcação da ACM, sem doença aterosclerótica, são alongadas e alinhadas com eixo axial do vaso, porém poligonais e sem orientação preferencial na bifurcação aterosclerótica.A bifurcação com aterosclerose apresenta uma monocamada endotelial altamente irregular e corrugada que invagina na luz do vaso e mostra características heterogêneas na superfície da membrana. A resolução das imagens de MEV foi superior àquela obtida nas imagens de AFM a baixa magnificação. Nas imagens de AFM, a parte lateral e as uniões celulares são pouco definidas e a varredura em altas magnificações diminui a resolução. Contudo, é possível determinar a topografia tridimensional da superfície celular, podendo-se, ao mesmo tempo, realizar estudos funcionais. Conclusão: Apesar da combinação única de alta resolução de imagem e operação sob condições próximas às fisiológicas, a AFM em amostras flexíveis apresenta resolução que depende do tipo de cantilever e do grau de hidratação da amostra. Por isso, em amostras vasculares as condições fisiológicas terão de ser estritamente reproduzidas...

Surgical treatment of patellar dislocation in children with Down syndrome: a 3- to 11-year follow-up study.

We report results of surgical treatment of ten knees affected by patellar dislocation in six children with Down syndrome. Four knees showed a dislocatable patella (grade III according to Dugdale), two a dislocated reducible patella (grade IV) and four a dislocated irreducible patella (grade V). Symptoms included frequent falls, limping and pain. In all the cases a Roux-Goldthwait-Campbell procedure was performed. Mean age at surgery was 10 years (range 6 years and 6 months to 13 years and 4 months). Patients were reviewed at an average follow-up of 8 years and 8 months (range 3 years and 6 months to 11 years and 5 months). None showed signs of recurrence of the dislocation. The median Lysholm score improved from 57.5 to 91/100. Statistical analysis showed a significant effectiveness of the procedure in improving function, and that surgery was significantly more effective in patients with more severe disability.

Congenital pseudarthrosis of the fibula and valgus deformity of the ankle in young children.

Treatment of cases of congenital pseudarthrosis of the fibula presenting with severe or progressive valgus deformity in early childhood is challenging. The purpose of the study presented was to analyse the deforming mechanisms to get therapeutic recommendations for this condition. A 2.5-year-old child was treated by resection of pseudarthrosis and distal tibiofibular fusion (Langenskiold operation) with autogenous bone grafting, associated with subtalar arthroereisis: progressive correction of the deformity was achieved. A 21-month-old child was treated with resection of pseudarthrosis, homologous bone grafting and fibular osteosynthesis: after failure, Langenskiold operation with autogenous bone grafting was performed and stabilization of the deformity was achieved. In young children with congenital pseudarthrosis of the fibula and valgus deformity, early surgical treatment is advisable: fibular ostheosynthesis has limited indications; distal tibiofibular fusion remains the treatment of choice, providing correction that may exceed the simple stabilization of deformity expected. Radiographic findings lead the authors to suggest that part of the effectiveness of the procedure is due to abnormal growth patterns.

Remodelling and overgrowth after conservative treatment for femoral and tibial shaft fractures in children.

One thousand nine hundred and eighty-four children who had received conservative treatment for shaft (diaphyseal and metadiaphyseal) fractures of lower limbs (1162 femoral, 822 tibial fractures) at an average age of 8.5 years (range 0-14 years) were reviewed by clinical and radiographic investigations at an average follow-up of 6.6 years (1-15 years). Particularly, two main features were evaluated: remodelling of (angular and rotational) deformities and post-traumatic overgrowth. Mechanisms underlying these processes are discussed, based on a review of the literature, and parameters conditioning their evolution are analysed. Finally, criteria for an acceptable reduction (and limits for residual deformities that may be tolerated) at the time of conservative treatment are proposed.

Prognostic factors in Ewing's sarcoma of the foot.

The outcome of treatment and prognostic factors were reviewed in 36 patients who had Ewing's sarcoma of the foot. The tumor was most common in the calcaneus (19 patients) and metatarsals (15 patients). Age, levels of lactate dehydrogenase, degree of anemia, tumor volume, type of surgery, and radiotherapy were not related to prognosis. Females with pain for less than 6 months, fever, high levels of erythrocyte sedimentation rate, and high levels of alkaline phosphatase showed a tendency for a poorer prognosis. The only observed prognostic factors are tumor site and treatment. Patients treated with four-drug neoadjuvant chemotherapy had the best survival. Four patients with metastatic disease at diagnosis died. Fourteen of 32 patients (44%) with localized Ewing's sarcoma were continuously disease-free at an average followup of 7 years.

Bilateral elbow malformation in a cat caused by radio-ulnar synostosis.

A 9-month-old neutered male cat was referred because of left forelimb lameness. Physical examination, laboratory analysis, and radiographic examination of the entire skeleton were performed. The radiographic diagnosis was bilateral radio-ulnar synostosis with secondary elbow malformation. A comparison between clinical and radiographic findings of the cat and those described in children affected by radio-ulnar synostosis is reported. Correlations and differences are discussed.