Three-dimensional,bioactive, biodegradable,polymer-bioactive glass composite scaffolds with improved mechanical properties support collagen synthesis and mineralization of human osteoblast-like cells in vitro

In the past decade, tissue engineering-based bone grafting has emerged as a viable alternative to biological and synthetic grafts. The biomaterial component is a critical determinant of the ultimate success of the tissue-engineered graft. Because no single existing material possesses all the necessary properties required in an ideal bone graft, our approach has been to develop a three dimensional (3-D), porous composite of polylactide-co-glycolide (PLAGA) and 45S5 bioactive glass (BG) that is biodegradable, bioactive, and suitable as a scaffold for bone tissue engineering (PLAGA-BG composite). The objectives of this study were to examine the mechanical properties of a PLAGA-BG matrix, to evaluate the response of human osteoblast-like cells to the PLAGA-BG composite, and to evaluate the ability of the composite to form a surface calcium phosphate layer in vitro. Structural and mechanical properties of PLAGA-BG were measured, and the formation of a surface calcium phosphate layer was evaluated by surface analysis methods. The growth and differentiation of human osteoblast-like cells on PLAGA-BG were also examined. A hypothesis was that the combination of PLAGA with BG would result in a biocompatible and bioactive composite, capable of supporting osteoblast adhesion, growth and differentiation, with mechanical properties superior to PLAGA alone. The addition of bioactive glass granules to the PLAGA matrix resulted in a structure with higher compressive modulus than PLAGA alone. Moreover, the PLAGA-BA composite was found to be a bioactive material, as it formed surface calcium phosphate deposits in a simulated body fluid (SBF), and in the presence of cells and serum proteins. The composite supported osteoblast-like morphology, stained positively for alkaline phosphatase, and supported higher levels of Type I collagen synthesis than tissue culture polystyrene controls. We have successfully developed a degradable, porous, polymer bioactive glass composite possessing improved mechanical properties and osteointegrative potential compared to degradable polymers of poly(lactic acid-glycolic acid) alone. Future work will focus on the optimization of the composite scaffold for bone tissue-engineering applications and the evaluation of the 3-D composite in an in vivo model.     

Resolution of acute lower extremity deep vein thrombosis with rivaroxaban compared to warfarin

Journal of Thrombosis and Thrombolysis - Thrombosis resolution is an important component of treatment for deep vein thrombosis (DVT) and multiple anticoagulants are now available. It is unknown...     

Molecular regulation of osteoblasts for tissue engineered bone repair

The use of biodegradable polymers in medicine and biomedical research is increasing. A key growth area has been the use of these materials in tissue engineering, especially for guided regeneration of bone and cartilage. Our interest has been in determining the mechanisms by which cellular attachment and growth occurs on these materials. In the current study, we examined human osteoblast cell adhesion, growth, and morphologic changes on polymeric scaffolds composed of polylactic-co-glycolic acid and polylactic acid materials. We examined these characteristics in association with measurements of levels of key adhesion integrin receptors in the presence and absence of antibodies against alpha2, alpha3, alpha4, alpha5, alpha6, and beta1 subunits, and the adhesion ligand peptides RGD (Arg-Gly-Asp) and RGE (Arg-Gly-Ser). At 2 hours, results showed initial cell adhesion was considerably decreased on polylactic-co-glycolic acid and polylactic acid in the presence of the alpha2 and beta1, antibodies with a 70% adhesion rate difference observed among the groups evaluated. Higher levels of inhibition were observed on polylactic-co-glycolic acid relative to polylactic acid, which may be correlated to a higher number of cells being able to interact with the surface initially. The presence of known competitive peptide (RGD) at 2 hours, revealed its ability to block cellular adhesion to these matrices relative to the control and noncompetitive peptide RGE on polylactic-co-glycolic acid matrices. Overall adhesion rate was affected by the presence of the integrin antibodies to the alpha2, alpha3, alpha4, alpha5, alpha6, and beta1 subunits with highest differences among polylactic-co-glycolic acid relative to its control, therefore suggesting that initial osteoblastic cell adhesion to commonly used biomaterials is regulated through integrin binding.     

Correlation of WOMAC and KOOS scores to tibiofemoral cartilage loss on plain radiography and 3 Tesla MRI: data from the osteoarthritis initiative

Purpose

The purpose of this study was to determine the correlation between the Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) and Knee Injury Osteoarthritis Outcomes scores (KOOS) and the degree of tibiofemoral cartilage loss on plain radiography and 3T magnetic resonance imaging (MRI). We hypothesize that these subjective outcome scores will have a significant correlation to quantitative joint space loss.

Methods

Data used in the preparation of this article were obtained from the osteoarthritis initiative (OAI) database (OAI public use data sets kMRI_QCart_Eckstein18 and kXR_QJSW_Duryea16). Four hundred and forty-five patients had WOMAC/KOOS scores, quantitative tibiofemoral joints space width on plain radiographs and quantitative tibiofemoral cartilage thickness and per cent full thickness cartilage loss on 3T MRI. Joint space width on plain radiographs was correlated to cartilage thickness on MRI, and WOMAC/KOOS scores were correlated to the degree of cartilage loss using Pearson correlation coefficients.

Results

There was a statistically significant correlation between medial and lateral compartment cartilage thickness on MRI and medial and lateral joint space width on plain radiography (r = 0.86, r = 0.80) (p < 0.001). KOOS knee pain score was significantly correlated to increasing per cent full thickness cartilage loss in the medial femoral compartment (r = 0.34) (p < 0.001). KOOS symptom score was significantly correlated to decreasing joint space width in the medial (r = 0.16) and lateral (r = 0.15) compartment and increasing per cent full thickness cartilage loss in the medial femoral compartment (r = 0.36) (p < 0.001). No WOMAC score was correlated to degree of joint space width, cartilage thickness or per cent full thickness cartilage loss (n.s).

Conclusion

The WOMAC and KOOS scores are poor indicators of tibiofemoral cartilage loss, with only the KOOS symptom and knee pain score being weakly correlated. Osteoarthritis is a multifactorial process and the need to treat patients based off their symptoms and rely on radiographs as confirmatory modalities, and not diagnostic modalities, when talking about OA and medical intervention.

Level of evidence

Level 2.     

Updates in venous thromboembolism management: evidence published in 2016

The management of venous thromboembolic disease (VTE) is rapidly evolving and staying updated on practice-changing evidence can be challenging. In an attempt to alleviate this daunting task, we sought to determine the most important practice-informing articles published in 2016 relevant to the non-specialist provider managing VTE. We performed a systematic search of the literature, limiting the search to a publication date of 2016 (see Supplementary Appendix). Two reviewers screened the 3819 resulting abstracts to identify high-quality, clinically relevant publications related to VTE management.

Two hundred sixteen full-text articles were considered for inclusion. The five authors used a modified Delphi method to reach consensus on inclusion of 7 articles for in-depth appraisal, following predetermined criteria of clinical relevance to non-specialist providers, potential for practice change, and strength of the evidence.     

Apixaban and Rivaroxaban in Patients With Acute Venous Thromboembolism

ObjectiveTo compare the clinical efficacy and safety of apixaban with those of rivaroxaban for the treatment of acute venous thromboembolism (VTE).Patients and MethodsConsecutive patients enrolled in the Mayo Thrombophilia Clinic Registry (between March 1, 2013, and January 30, 2018) and treated with apixaban or rivaroxaban for acute VTE were followed forward in time. The primary efficacy outcome was VTE recurrence. The primary safety outcome was major bleeding; the second safety outcome was clinically relevant nonmajor bleeding (CRNMB); and the third was a composite of major bleeding or CRNMB.ResultsWithin the group of 1696 patients with VTE enrolled, 600 (38%) were treated either with apixaban (n=302, 50%) or rivaroxaban (n=298, 50%) within the first 14 days of VTE diagnosis and who completed at least 3 months of therapy or had a study event. Recurrent VTE was diagnosed in 7 patients (2.3%) treated with apixaban and in 6 (2%) treated with rivaroxaban (adjusted hazard ratio [aHR], 1.4; 95% CI, 0.5-3.8). Major bleeding occurred in 11 patients (3.6%) receiving apixaban and in 9 patients (3.0%) receiving rivaroxaban (aHR, 1.2; 95% CI, 0.5-3.2). Clinically relevant nonmajor bleeding was diagnosed in 7 patients (2.3%) receiving apixaban and in 20 (6.7%) receiving rivaroxaban (aHR, 0.4; 95% CI, 0.2-0.9). The rates of composite major bleeding or CRNMB were similar (aHR, 0.6; 95% CI, 0.3-1.2). Most study events occurred in patients with cancer.ConclusionIn the setting of a standardized, guideline-directed, patient-oriented clinical practice, the efficacy and safety of apixaban and rivaroxaban for the treatment of acute VTE were comparable.     

In vivo biodegradability and biocompatibility evaluation of novel alanine ester based polyphosphazenes in a rat model

Amino acid ester substituted polyphosphazenes are attractive candidates for various biomedical applications because of their biocompatibility, controllable hydrolytic degradation rates, and nontoxic degradation products. In this study, the biocompatibility of three L-alanine ethyl ester functionalized polyphosphazenes was evaluated in a subcutaneous rat model. The polymers used in the study were poly[bis(ethylalanato)phosphazene] (PNEA), poly[(50% ethylalanato) (50% methylphenoxy) phosphazene] (PNEA(50)mPh(50)), and poly[(50% ethylalanato)(50% phenyl phenoxy) phosphazene] (PNEA(50)PhPh(50)). Polymer disks of diameter 7.5 mm were prepared by a solvent evaporation technique and were implanted subcutaneously in rats. After 2, 4, and 12 weeks, the polymer along with the surrounding tissues were excised, prepared, and viewed by light microscopy to evaluate the tissue responses of the implanted polymers. The tissue responses were classified as minimal, mild, or moderate, based on a biocompatibility scheme developed in our laboratory. Minimal inflammation was characterized by the presence of few neutrophils, erythrocytes, and lymphocytes; mild response was characterized by the predominant presence of macrophages, fibroblasts, or giant cells; and moderate inflammation was characterized by the abundance of macrophages, giant cells, and by the presence of tissue exudates. The in vivo degradation profiles of the polymers at various time points were evaluated by gel permeation chromatography (GPC). PNEA and PNEA(50)mPh(50) matrices elicited varying levels of tissue responses during the 12-week implantation period. At 2 weeks both polymers evoked a moderate response, and by 12 weeks the response was found to be mild. However, PNEA(50)PhPh(50) elicited a mild response at the end of 2 weeks and demonstrated a further decreased inflammatory response after 12 weeks. The in vivo degradation of the polymers was followed by determining the molecular weights of the explanted polymer disks. PNEA and PNEA(50)mPh(50) disks showed significant decrease in molecular weight after 2 weeks of implantation. The molecular weights of PNEA and PNEA(50)mPh(50) residues could not be determined by GPC after 12 weeks of implantation because of almost complete degradation. On the other hand the in vivo degradation of PNEA(50)PhPh(50) was found to be slow, with a 63% loss in molecular weight in 12 weeks. Furthermore, this polymer maintained its shape and structure during the entire study. Thus, these polymers demonstrated excellent tissue compatibility and in vivo biodegradability and can be potential candidates for various biomedical applications.     

Single walled carbon nanotube composites for bone tissue engineering

The purpose of this study was to develop single walled carbon nanotubes (SWCNT) and poly lactic‐co‐glycolic acid (PLAGA) composites for orthopedic applications and to evaluate the interaction of human stem cells (hBMSCs) and osteoblasts (MC3T3‐E1 cells) via cell growth, proliferation, gene expression, extracellular matrix production and mineralization. PLAGA and SWCNT/PLAGA composites were fabricated with various amounts of SWCNT (5, 10, 20, 40, and 100 mg), characterized and degradation studies were performed. Cells were seeded and cell adhesion/morphology, growth/survival, proliferation and gene expression analysis were performed to evaluate biocompatibility. Imaging studies demonstrated uniform incorporation of SWCNT into the PLAGA matrix and addition of SWCNT did not affect the degradation rate. Imaging studies revealed that MC3T3‐E1 and hBMSCs cells exhibited normal, non‐stressed morphology on the composites and all were biocompatible. Composites with 10 mg SWCNT resulted in highest rate of cell proliferation (p < 0.05) among all composites. Gene expression of alkaline phosphatase, collagen I, osteocalcin, osteopontin, Runx‐2, and Bone Sialoprotein was observed on all composites. In conclusion, SWCNT/PLAGA composites imparted beneficial cellular growth capabilities and gene expression, and mineralization abilities were well established. These results demonstrate the potential of SWCNT/PLAGA composites for musculoskeletal regeneration and bone tissue engineering (BTE) and are promising for orthopedic applications. © 2013 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 31:1374–1381, 2013     

Xenotransplantation in orthopaedic surgery

We define xenotransplantation as including any procedure that involves the transplantation, implantation, or infusion into a human recipient of cells, tissues, or organs from a nonhuman animal source or of human body fluids, cells, tissues, or organs that have had ex vivo contact with nonhuman animal cells, tissues, or organs. The current FDA definition of xenotransplantation relates to procedures involving live, nonhuman materials. The proposed use of xenotransplanted tissues for treatment of a wide variety of human diseases is increasing. In orthopaedic surgery, a number of xeno-based products for treatment of musculoskeletal conditions have been cleared by the FDA. Commercially available products include those used as alternatives for bone, cartilage, and soft-tissue repair. Most xenografts are from bovine- or porcine-derived sources. Studies internationally have demonstrated a low relative risk of disease transmission, although there is concern regarding the potential for transmission into humans of agents not considered pathogenic or not detected in animals.