Enrique Gómez-Barrena

Topical intra-articular compared with intravenous tranexamic acid to reduce blood loss in primary total knee replacement: a double-blind, randomized, controlled, noninferiority clinical trial.

BACKGROUND Abundant literature regarding the use of intravenous tranexamic acid (TXA) in primary total knee replacement is available. Randomized controlled trials have confirmed the efficacy of topical TXA compared with placebo, but the comparison between topical and intravenous TXA is unclear. The present study was designed to verify noninferior efficacy and safety of topical intra-articular TXA compared with intravenous TXA in primary total knee replacement with cemented implants. METHODS A Phase-III, single-center, double-blind, randomized, controlled clinical trial was performed to compare topical intra-articular TXA (3 g of TXA in 100 mL of physiological saline solution) with two intravenous doses of TXA (15 mg/kg in 100 mL of physiological saline solution, one dose before tourniquet release and another three hours after surgery) in a multimodal protocol for blood loss prevention. The primary outcome was the blood transfusion rate, and the secondary outcomes included visible blood loss (as measured in the drain) at twenty-four hours postoperatively and invisible blood loss (as estimated from the Nadler formula) at forty-eight hours postoperatively. The sample size of seventy-eight patients was calculated to give a statistical power of 99% for demonstrating noninferiority. Thirty-nine patients each were allocated to receive topical intra-articular TXA (the experimental group) and intravenous TXA (the control group); there were no significant differences in demographics or preoperative laboratory values between the groups. Noninferiority was estimated by comparing the confidence intervals with a delta of 10%. Student t and Mann-Whitney tests were used to assess the significance of any differences. RESULTS The transfusion rate was zero in both groups; thus, noninferiority was demonstrated for the primary efficacy end point, suggesting equivalence. Noninferiority was also demonstrated for the secondary efficacy end points. Drain blood loss at twenty-four hours was 315.6 mL (95% confidence interval [CI], 248.5 to 382.7 mL) in the experimental group and 308.1 mL (95% CI, 247.6 to 368.5 mL) in the control group (p = 0.948, Mann-Whitney). Also, estimated blood loss at forty-eight hours was 1259.0 mL (95% CI, 1115.6 to 1402.3 mL) in the experimental group and 1317.9 mL (95% CI, 1175.4 to 1460.4 mL) in the control group (p = 0.837, Mann-Whitney). No significant safety differences were seen between groups. CONCLUSIONS Topical administration of TXA according to the described protocol demonstrated noninferiority compared with intravenous TXA, with no safety concerns. This randomized controlled trial supports the topical intra-articular administration of TXA in primary total knee replacement with cemented implants. LEVEL OF EVIDENCE Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Bone regeneration: stem cell therapies and clinical studies in orthopaedics and traumatology.

•  Introduction •  Characterization of cells for bone regeneration in human beings •  State of the art in bone tissue engineering ‐  Biomaterials for scaffolding mesenchymal stem cells ‐  Future trends in bone tissue engineering •  Clinical targets for cell therapy in orthopaedics ‐  Current clinical problems and therapeutic approaches ‐  Potential clinical applications of cell based therapies for bone repair ‐  Data reported in clinical studies •  Selected paediatric bone disorders and cellular therapies ‐  Inborn errors of bone metabolism and cellular therapy ‐  Degenerative bone disorders in childhood •  Ethical aspects of EU clinical trials ‐  Ethics related to information and consent ‐  Approval of the studies ‐  Ethics related to privacy/data protection ‐  Ethics related to the risk‐benefit assessment ‐  Ethics related to protection of the health of persons involved in clinical trials ‐  Ethics related to transparency regarding research results •  Future directions and remarks

Usefulness of SBA-15 mesoporous ceramics as a delivery system for vancomycin, rifampicin and linezolid: a preliminary report

Bone infections are a challenge for modern medicine. The most common pathogen is Staphylococcus aureus, which usually develops a biofilm inside the infected bone. Local release of antibiotics within the infected tissue may diminish this problem because high concentrations of the antibiotic would be delivered to the required place. This study was carried out to evaluate silica-based mesoporous material SBA-15 as a delivery system for three antibiotics with activity against S. aureus, namely vancomycin, rifampicin and linezolid, alone or in combination. SBA-15 disks were loaded with antibiotics by adsorption using a 1000 mg/L solution. Measurements of biological activity were carried out by bioassay tests, and antibiotic release was monitored by high-performance liquid chromatography (HPLC). In all cases, the ceramic disks released most of the antibiotics at the initial stage of the experiments, with concentrations above the susceptibility breakpoints. The most active antibiotic was rifampicin, with an active concentration of 96.14 mg/L at 24 h, followed by linezolid (7.2 mg/L) and vancomycin (5.5 mg/L). In the HPLC measurements, the antibiotic that showed the best release was linezolid, followed by vancomycin; rifampicin alone could not be measured by HPLC with precision. Taking into account all these results, the antibiotic that remains most active after loading and release is vancomycin (77.46%), followed by linezolid (24%). The results presented here demonstrate the efficacy of SBA-15 bioceramics for local release of antibiotics, which could be of interest in the context of bone infection.

Doped TiO2 anodic layers of enhanced antibacterial properties

Ti-6Al-4V joint replacement implants foster uncemented fixation in orthopaedic surgery. However, bacterial colonization competes with host cells and ultimately may produce implant-related difficult-to-treat infections, justifying the efforts to obtain infection-resistant materials. In a previous work, the authors demonstrated the antibacterial properties of anodic fluoride-TiO2 nanostructured layers on Ti-6Al-4V alloy. In this work, the anodizing bath has been modified in order to grow fluoride-TiO2 barrier layers (FBL). A bacterial adherence protocol, run with reference and six different clinical strains of Staphylococcus aureus and Staphylococcus epidermidis, showed a statistically significant decrease in the percentage of covered surface (p<0.0001, Kruskal-Wallis test) for FBL specimens when compared with non fluoride-containing specimens, i.e. chemically polished Ti-6Al-4V and F-free TiO2 barrier layers. The results obtained on the F-barrier layers allowed discrimination between the effects of the presence of fluoride in the layer and the layer nanostructure on bacterial adhesion.

Compression behaviour of biphasic calcium phosphate and biphasic calcium phosphate-agarose scaffolds for bone regeneration

There is an acknowledged need for shaping 3-D scaffolds with adequate porosity and mechanical properties for biomedical applications. The mechanical properties under static and cyclic compressive testing of dense and designed porous architecture bioceramic scaffolds based on the biphasic calcium phosphate (BCP) systems and BCP-agarose systems have been evaluated. The dense and designed porous architecture scaffolds in BCP systems exhibited a brittle behaviour. Agarose, a biocompatible and biodegradable hydrogel, has been used to shape designed architecture ceramic-agarose scaffolds following a low-temperature shaping method. Agarose conferred toughness, ductility and a rubbery consistency for strains of up to 60% of in ceramic BCP-agarose systems. This combination of ceramic and organic matrix helps to avoid the inherent brittleness of the bioceramic and enhances the compression resistance of hydrogel. The presence of mechanical hysteresis, permanent deformation after the first cycle and recovery of the master monotonous curve indicate a Mullins-like effect such as that observed in carbon-filled rubber systems. We report this type of mechanical behaviour, the Mullins effect, for the first time in bioceramics and bioceramic-agarose systems.

Influence of the nanostructure of F-doped TiO2 films on osteoblast growth and function

The aim of this study was to evaluate the proliferation and mineralization ability of mouse osteoblastic MC3T3-E1 cells on F-containing TiO2 films with different morphology and nanostructure that previously confirmed antibacterial properties. F-containing TiO2 films were fabricated by anodizing Ti-6Al-4V alloy ELI -grade 23. By using a mixture of H2SO4/HF acid at 20 V for 5 and 60 min, a TiO2 film grows with nanoporous (NP) and nanotubular (NT) features, characterized with a pore diameter of 20 and 100 nm, respectively. Fluoride-TiO2 barrier films (FBL) were produced in 1M NH4H2PO4/0.15M NH4F solution at constant voltage controlled at 20 V for 120 min. The amount of F incorporated in the nanostructured oxide films was 6 at % and of 4 at %, for the NP and NT, respectively, while for the FBL film was 12 at %. MC3T3-E1 cells exhibited different behavior when seeded and grown onto these surfaces. Thus, F-doped TiO2 films with NP structures increased proliferation as well as osteogenic gene expression and the mineralization capacity of these osteoblastic cells. These results confirm that anodizing process is suitable to fabricate multifunctional surfaces on Ti-6Al-4V alloy with improved not only antibacterial but also osteogenic properties useful for bone fixation of prosthetic devices

Parathyroid hormone-related protein (107-111) improves the bone regeneration potential of gelatin–glutaraldehyde biopolymer-coated hydroxyapatite

Biopolymer-coated nanocrystalline hydroxyapatite (HA) made as macroporous foams which are degradable and flexible are promising candidates as orthopaedic implants. The C-terminal (107-111) epitope of parathyroid hormone-related protein (PTHrP) exhibits osteogenic properties. The main aim of this study was to evaluate whether PTHrP (107-111) loading into gelatin-glutaraldehyde biopolymer-coated HA (HAGlu) scaffolds would produce an optimal biomaterial for tissue engineering applications. HAGlu scaffolds with and without PTHrP (107-111) were implanted into a cavitary defect performed in both distal tibial metaphysis of adult rats. Animals were sacrificed after 4 weeks for histological, microcomputerized tomography and gene expression analysis of the callus. At this time, bone healing occurred only in the presence of PTHrP (107-111)-containing HAGlu implant, related to an increase in bone volume/tissue volume and trabecular thickness, cortical thickness and gene expression of osteocalcin and vascular cell adhesion molecule 1, but a decreased gene expression of Wnt inhibitors, SOST and dickkopf homolog 1. The autonomous osteogenic effect of the PTHrP (107-111)-loaded HAGlu scaffolds was confirmed in mouse and human osteoblastic cell cultures. Our findings demonstrate the advantage of loading PTHrP (107-111) into degradable HAGlu scaffolds for achieving an optimal biomaterial that is promising for low load bearing clinical applications.

Molecular Diagnosis of Prosthetic Joint Infection

Diagnosis of Prosthetic Joint Infection remains as a challenge in modern medicine. Conventional techniques lead to the diagnosis of many patients with a classical infectious syndrome, but differential diagnosis with other entities (particularly aseptic failure) is still a problem. Several molecular markers have been studied in the diagnosis of infection (like cytokines, procalcitonin, specific IgG, sICAM-1, VEGF or alpha2-Macroglobulin), and even for microbiological diagnosis (lipid S, PIA, icaADBC operon), with variable success. PCR-based genetic amplification procedures have also been studied for the detection of microbial genes in different clinical samples, and will be probably included in the next future as part of the diagnostic schemes for this kind of infections.

Bacterial adhesion on biomedical surfaces covered by micrometric silver Islands

A set of Cu-Mn-O and Ag-Cu-Mn-O films were sputter-deposited onto polished Ti-6Al-4V coupons and the microbiological adherence of Staphylococcus sp. was studied in these biomedical surfaces modified by using advanced ternary and quaternary oxides, these latter incorporated micrometric silver islands. Silver is known to have a natural biocidal character and its presence in the surface of Ti-6Al-4V forming large micrometric islands. In principle, predicted to enhance the antimicrobial properties of biomedical surfaces. Microbial adhesion tests were performed using collection strains and six clinical Staphylococcus aureus and Staphylococcus epidermidis strains. The adherence study was performed using a previously published protocol by Kinnari et al. Collection strains and clinical strains showed decreased adherence to modified materials; however, only on the clinical strains were there statistically significant differences between Cu-Mn-O and Ag-Cu-Mn-O containing silver islands. Nanocrystalline silver dissolves and releases both Ag(+) and Ag(0) whereas other silver sources release only Ag+. We can conclude that nanocrystalline silver coating, confirmed by XRD, appears to alter the biological properties of the solution, particularly antimicrobial activity.

Bacterial Adherence to Biomaterials Used in Surgical Procedures

Bacterial adherence is a complex process that involves different phases, which end with bacteria being firmly adhered to a material’s surface. Different mechanisms are involved in this process, including different molecules in the bacterial cell wall, and also different properties of the material. These latter properties can be modified to minimize bacterial adhesion, a strategy that is currently being developed. In this chapter we review the currently available data on bacterial adherence, and describe some of the strategies used to overcome this phenomenon.