Enhanced angiogenesis and increased bone turnover characterize bone marrow lesions in osteoarthritis at the base of the thumb.

OBJECTIVES: Little is known about tissue changes underlying bone marrow lesions (BMLs) in non-weight-bearing joints with osteoarthritis (OA). Our aim was to characterize BMLs in OA of the hand using dynamic histomorphometry. We therefore quantified bone turnover and angiogenesis in subchondral bone at the base of the thumb, and compared the findings with control bone from hip OA. METHODS: Patients with OA at the base of the thumb, or the hip, underwent preoperative MRI to assess BMLs, and tetracycline labelling to determine bone turnover. Three groups were compared: trapezium bones removed by trapeziectomy from patients with thumb base OA (n = 20); femoral heads with (n = 24); and those without (n = 9) BMLs obtained from patients with hip OA who underwent total hip arthroplasty. RESULTS: All trapezium bones demonstrated MRI-defined BMLs. Compared with femoral heads without BMLs, the trapezia demonstrated significantly higher bone turnover (mean sd 0.2 (0.1) versus 0.01 (0.01) µm3/µm2/day), mineralizing surface (18.5% (13.1) versus 1.4% (1.3)) and vascularity (5.2% (1.1) versus 1.2% (0.6)). Femoral heads with BMLs exhibited higher bone turnover (0.3 (0.2) versus 0.2 (0.1) µm3/µm2/day), a higher mineralization rate (26.6% (10.6) versus 18.6% (11.9)) and greater trabecular thickness (301.3 µm (108) versus 163.6 µm (24.8)) than the trapezia. CONCLUSION: Bone turnover and angiogenesis were enhanced in BMLs of both the thumb base and hip OA, of which the latter exhibited the highest bone turnover. Thus, the increase in bone turnover in weight-bearing joints like the hip may be more pronounced than less mechanically loaded osteoarthritic joints demonstrating BMLs. The histological changes observed may explain the water signal from BMLs on MRI.Cite this article: M. Shabestari, N. J. Kise, M. A. Landin, S. Sesseng, J. C. Hellund, J. E. Reseland, E. F. Eriksen, I. K. Haugen. Enhanced angiogenesis and increased bone turnover characterize bone marrow lesions in osteoarthritis at the base of the thumb. Bone Joint Res 2018;7:406-413. DOI: 10.1302/2046-3758.76.BJR-2017-0083.R3.

Mineralized alginate hydrogels using marine carbonates for bone tissue engineering applications.

The search for an ideal bone tissue replacement has led to the development of new composite materials designed to simulate the complex inorganic/organic structure of bone. The present work is focused on the development of mineralized calcium alginate hydrogels by the addition of marine derived calcium carbonate biomineral particles. Following a novel approach, we were able to obtain calcium carbonate particles of high purity and complex micro and nanostructure dependent on the source material. Three different types of alginates were selected to develop inorganic/organic scaffolds in order to correlate alginate composition with scaffold properties and cell behavior. The incorporation of calcium carbonates into alginate networks was able to promote extracellular matrix mineralization and osteoblastic differentiation of mesenchymal stem cells when added at 7 mg/ml. We demonstrated that the selection of the alginate type and calcium carbonate origin is crucial to obtain adequate systems for bone tissue engineering as they modulate the mechanical properties and cell differentiation.

The burden of illness in patients with hyponatraemia in Sweden: a population-based registry study.

BACKGROUND: Hyponatraemia (HN; serum sodium level < 135 mmol/l) is the most common electrolyte disturbance seen in clinical practice, and is associated with varying spectrum of symptoms. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most common aetiology in hospitalised patients, and can be caused by several different underlying conditions. AIMS: The objectives of this study were to retrospectively examine the baseline characteristics, clinical outcomes and hospital resource utilisation of patients with HN and/or SIADH in Sweden over a 10-year period from 2001 to 2011. Additional analysis was performed on subpopulations of patients with hip fracture, pneumonia and small cell lung cancer (SCLC) to see if trends in outcomes were consistent across a broad range of aetiologies commonly associated with the condition. METHODS: Patient information was taken from the Swedish National Patient Registry, the Swedish Cancer Registry, the Swedish Cause of Death Register and the Swedish Prescribed Drug Register. A total of 34,537 patients (4.38%) were identified with HN and/or SIADH, with the incidence and prevalence rising over the 10-year study period. RESULTS: Of the 34,537 patients identified, 841 had hip fracture, 2635 had pneumonia and 106 had SCLC. Compared with matched control patients, those with HN and/or SIADH had a longer length of hospital stay, a higher re-admission rate and a shorter time to re-admission. CONCLUSIONS: This study showed that HN and/or SIADH negatively impact patient outcomes and healthcare resources related to hospital stay irrespective of the underlying cause. The impact of HN is not confined to the initial hospitalisation, as re-admission rates are also affected.

Effective genetic modification and differentiation of hMSCs upon controlled release of rAAV vectors using alginate/poloxamer composite systems.

Viral vectors are common tools in gene therapy to deliver foreign therapeutic sequences in a specific target population via their natural cellular entry mechanisms. Incorporating such vectors in implantable systems may provide strong alternatives to conventional gene transfer procedures. The goal of the present study was to generate different hydrogel structures based on alginate (AlgPH155) and poloxamer PF127 as new systems to encapsulate and release recombinant adeno-associated viral (rAAV) vectors. Inclusion of rAAV in such polymeric capsules revealed an influence of the hydrogel composition and crosslinking temperature upon the vector release profiles, with alginate (AlgPH155) structures showing the fastest release profiles early on while over time vector release was more effective from AlgPH155+PF127 [H] capsules crosslinked at a high temperature (50°C). Systems prepared at room temperature (AlgPH155+PF127 [C]) allowed instead to achieve a more controlled release profile. When tested for their ability to target human mesenchymal stem cells, the different systems led to high transduction efficiencies over time and to gene expression levels in the range of those achieved upon direct vector application, especially when using AlgPH155+PF127 [H]. No detrimental effects were reported on either cell viability or on the potential for chondrogenic differentiation. Inclusion of PF127 in the capsules was also capable of delaying undesirable hypertrophic cell differentiation. These findings are of promising value for the further development of viral vector controlled release strategies.

The synergistic effect of VEGF and biomorphic silicon carbides topography on in vivo angiogenesis and human bone marrow derived mesenchymal stem cell differentiation.

Topographical features of biomaterials are able to modulate cell attachment, spreading and differentiation. The addition of growth factors to implantable biomaterials can modify these cellular responses, enhancing their therapeutic potential. The aim of this research is to establish the influence of biomorphic silicon carbide ceramics (bioSiCs) surface topography on the proliferation and osteoblastic differentiation of mesenchymal stem cells and the potential synergistic effect of the ceramic porous structure together with vascular endothelial growth factor loading (VEGF) on the surface mediated osteoblastic differentiation. Three porous bioSiCs with important differences in their microstructure were obtained from different natural precursors. Samples loaded with or without VEGF through ionic interactions were cultured with human umbilical vein endothelial cells (HUVEC) or bone marrow derived mesenchymal stem cells (hMSCs). Cell behaviour and protein activity with regard to bioSiC porous structure and surface properties were analysed. An in vivo model (Chick Chorioallantoic Membrane; CAM) was used to assess the capability of the VEGF loaded systems to promote angiogenesis. Experimental data show that loaded systems were able to control the release of VEGF for up to 15 d ensuring the activity of the protein, increasing the proliferation of HUVECs and the formation of new blood vessels in the CAM. It was found that the selection of bioSiCs with a higher pore size promoted a higher concentration of osteoblastic differentiation markers of MSCs cultured on the surface of bioSiCs. Furthermore, the addition of VEGF to the systems was able to promote a faster osteoblastic differentiation according to the qPCR results, suggesting a synergy between both the surface properties and the controlled release of the growth factor. The VEGF loaded sapelli bioSiC was found to be the most promising material for bone tissue engineering applications.

Controlled release of indomethacin from alginate-poloxamer-silicon carbide composites decrease in-vitro inflammation.

Composites of biomorphic silicon carbides (bioSiCs) and hydrogels are proposed in order to obtain materials able to load and release poor soluble drugs with application in bone pathologies therapy. Hydrogels composed by alginate and poloxamer were loaded with indomethacin, incorporated into the ceramics and crosslinked. The indomethacin release profile is dependent on the microstructure of the bioSiC selected. The loaded oak and sapelli bioSiCs composites have adequate release profiles to promote the decreasing of the secretion of pro-inflammatory cytokines in LPS stimulated macrophages, showing stronger anti-inflammatory effects than pine bioSiC composites. The released indomethacin is able to modulate the degradation of chondrocytes extracellular matrix and promote the formation of new collagen by osteoarthritic chondrocytes. Particles derived from mechanical wear of biomorphic silicon carbides do not show high toxicity, being similar to the zirconia particles.

Antibacterial properties of laser spinning glass nanofibers.

A laser-spinning technique has been used to produce amorphous, dense and flexible glass nanofibers of two different compositions with potential utility as reinforcement materials in composites, fillers in bone defects or scaffolds (3D structures) for tissue engineering. Morphological and microstructural analyses have been carried out using SEM-EDX, ATR-FTIR and TEM. Bioactivity studies allow the nanofibers with high proportion in SiO2 (S18/12) to be classified as a bioinert glass and the nanofibers with high proportion of calcium (ICIE16) as a bioactive glass. The cell viability tests (MTT) show high biocompatibility of the laser spinning glass nanofibers. Results from the antibacterial activity study carried out using dynamic conditions revealed that the bioactive glass nanofibers show a dose-dependent bactericidal effect on Sthaphylococcus aureus (S. aureus) while the bioinert glass nanofibers show a bacteriostatic effect also dose-dependent. The antibacterial activity has been related to the release of alkaline ions, the increase of pH of the medium and also the formation of needle-like aggregates of calcium phosphate at the surface of the bioactive glass nanofibers which act as a physical mechanism against bacteria. The antibacterial properties give an additional value to the laser-spinning glass nanofibers for different biomedical applications, such as treating or preventing surgery-associated infections.

Key parameters in blood-surface interactions of 3D bioinspired ceramic materials.

Direct contact of materials with blood components may trigger numerous processes which ultimately lead to hemolysis, clot formation and recruitment of inflammatory cells. In this study, the blood-surface interactions for two inert bioinspired ceramic scaffolds obtained from natural resources; biomorphic carbon and silicon carbides (bioSiC) from different origins have been studied. The response of the blood in contact with carbon is well known, however little has been identified on the influence of their 3D porous structure. Moreover, to our knowledge, there is no reference in the literature about the hemocompatibility of biomorphic silicon carbide as a porous scaffold. The experimental results showed the surface energy to be crucial to evaluate the hemocompatibility of a material however the surface topography and material porosity are also parameters to be considered. Surface roughness modifies clot formation whereas for protein adsorption total sample porosity seems to be the key parameter to be considered for hydrophilic materials (biomorphic silicon carbides), while the size of the pores determines the hemolytic response.

Suitability of Biomorphic Silicon Carbide Ceramics as Drug Delivery Systems against Bacterial Biofilms.

The present work is aimed at getting a new insight into biomorphic silicon carbides (bioSiCs) as bone replacement materials. BioSiCs from a variety of precursors were produced, characterized, and loaded with a broad-spectrum antibiotic. The capacity of loaded bioSiCs for preventing and/or treating preformed S. aureus biofilms has been studied. The differences in precursor characteristics are maintained after the ceramic production process. All bioSiCs allow the loading process by capillarity, giving loaded materials with drug release profiles dependent on their microstructure. The amount of antibiotic released in liquid medium during the first six hours depends on bioSiC porosity, but it could exceed the minimum inhibitory concentration of Staphylococcus aureus, for all the materials studied, thus preventing the proliferation of bacteria. Differences in the external surface and the number and size of open external pores of bioSiCs contribute towards the variations in the effect against bacteria when experiments are carried out using solid media. The internal structure and surface properties of all the systems seem to facilitate the therapeutic activity of the antibiotic on the preformed biofilms, reducing the number of viable bacteria present in the biofilm compared to controls.

Using machine learning for improving knowledge on antibacterial effect of bioactive glass.

The aim of this work was to find relationships between critical bioactive glass characteristics and their antibacterial behaviour using an artificial intelligence tool. A large dataset including ingredients and process variables of the bioactive glasses production, bacterial characteristics and microbiological experimental conditions was generated from literature and analyzed by neurofuzzy logic technology. Our findings allow an explanation on the variability in antibacterial behaviour found by different authors and to obtain general conclusions about critical parameters of bioactive glasses to be considered in order to achieve activity against some of the most common skin and implant surgery pathogens.

Smart design of intratumoral thermosensitive ß-lapachone hydrogels by Artificial Neural Networks.

This study presents Artificial Neural Networks (ANN) as a tool for designing injectable intratumoral formulations of the anticancer drug ß-lapachone. This methodology permits insight into the interactions between variables and determines the design space of the formulation without the restrictions of an experimental design. An ANN model for two critical parameters of the formulations; the amount of solubilized drug and gel temperature was developed and validated. The model allowed an understanding of interactions between ingredients in the formulation and the fundamental phenomena as the formation of polypseudorotaxanes to be detected and quantified.

Human papillomavirus subtypes in oral lesions compared to healthy oral mucosa.

BACKGROUND: Human papillomaviruses (HPV) are involved in the etiology of cervix cancer, but it is still unclear whether they play a role in related oral lesions. OBJECTIVES: The presence of HPV in oral leukoplakia biopsies (n=50) and oral squamous carcinoma biopsies (n=50) was compared to normal oral mucosa swabs (n=50) for the purpose of indicating a possible etiological role for the virus. STUDY DESIGN: DNA was extracted from tissue biopsies and from mucosa swabs of control samples. Nested PCR was performed with primers targeting conserved sequences within the capsid gene L1. PCR products were sequenced to identify the HPV genotype. RESULT: The results reveal a profile of low-risk HPV genotypes in oral leukoplakia similar to that in healthy controls, while HPV was less frequently observed in oral squamous carcinoma. CONCLUSIONS: HPV does not seem to represent an important causal factor for the development of oral leukoplakia or oral squamous carcinoma.

Bio-inspired porous SiC ceramics loaded with vancomycin for preventing MRSA infections.

Implant-related infections are a serious complication in orthopaedic and dental surgery resulting in prolonged hospitalization, high medical costs and patient mortality. The development of porous implants loaded with antibiotics may enable a local delivery for preventing surface colonization and biofilm formation. A new generation of bio-derived porous ceramic material that mimics hierarchical structures from Nature was evaluated. Silicon carbide ceramics derived from Sapelli wood (bioSiC) were obtained by pyrolysis of Entandrophragma cylindricum wood followed by infiltration with molten silicon. This process renders disks that keep the bimodal pore size distribution (3 and 85 µm) of the original material and are highly cytocompatible (BALB/3T3 cell line). The ability of the bio-ceramic to load the antimicrobial agent vancomycin was evaluated by immersion of disks in drug solutions covering a wide range of concentrations. The disks released at pH 7.4 an important amount of drug during the first 2 h (up to 11 mg/g bioSiC) followed by a slower release, which is related to the presence of macro- and mesopores. Finally, the anti-biofilm effect against methicillin resistant Staphylococcus aureus was assessed and a considerable reduction (92%) of the bacterial film was observed. Results highlight the bioSiC potential as component of medicated medical devices.

Artificial neural networks as an alternative to the traditional statistical methodology in plant research.

In this work, we compared the unique artificial neural networks (ANNs) technology with the usual statistical analysis to establish its utility as an alternative methodology in plant research. For this purpose, we selected a simple in vitro proliferation experiment with the aim of evaluating the effects of light intensity and sucrose concentration on the success of the explant proliferation and finally, of optimizing the process taking into account any influencing factors. After data analysis, the traditional statistical procedure and ANNs technology both indicated that low light treatments and high sucrose concentrations are required for the highest kiwifruit microshoot proliferation under experimental conditions. However, this particular ANNs software is able to model and optimize the process to estimate the best conditions and does not need an extremely specialized background. The potential of the ANNs approach for analyzing plant biology processes, in this case, plant tissue culture data, is discussed.

A comparison of trehalose dihydrate and mannitol as stabilizing agents for dicalcium phosphate dihydrate based tablets.

This study investigated the possible utility of trehalose dihydrate (TD) as a tablet stabilizing agent. Acetylsalicylic acid was used as the model hydrolyzable drug and dicalcium phosphate dihydrate (DCPD) as the base excipient, because it is well documented that ASA/DCPD tablets are unstable during storage at low temperature and high relative humidity; DCPD is usually combined with mannitol in order to improve tablet stability. Tablets comprising DCPD, 10% ASA, and 0%, 10%, or 20% w/w of TD were prepared by direct compression and stored at 35 degrees C and 82.9% relative humidity for 6 months. Additionally, control tablets with DCPD and ASA, only, or with DCPD, ASA and 20% mannitol, were also evaluated. At predetermined time intervals, formulations were tested for drug content, mechanical, microstructural, and drug dissolution properties. Additionally, thermal analyses and ASA solution stability studies were carried out. Results reveal that both TD and mannitol significantly reduce degradation of ASA included in DCPD-based tablets, but neither effectively protects against the marked decline in tablet mechanical properties on aging. The ASA stabilization effects of TD and mannitol were also observed in solution, indicating an interaction between these sugars and ASA.

Scaleup of a pharmaceutical granulation in planetary mixers.

The scaleup of a pharmaceutical granulation in a series of planetary mixers with increasing bowl capacity between 5 and 200 liters has been studied by applying the classical dimensionless numbers of Power, Reynolds, and Froude to define the power consumption profile of each mixer as a function of the processing conditions in dimensionless form. Experiments were performed using a formulation based on dicalcium phosphate dihydrate containing pregelatinized starch, with water being added at a fixed rate. Samples were taken at different power consumptions and assessed using mixer torque rheometry. Geometrically similar machines gave the same dimensionless relationship, but when similarity was compromised by the use of modified bowls and blades, different relationships occurred. The results show that, for geometrically similar machines, it is possible to calculate the power consumption at a predefined granulation endpoint at any given operating condition at any scale.

In-laboratory removal of femoral sheath following protamine administration in patients having intracoronary stent implantation.

Two hundred twenty-eight patients with successful coronary stent implantation were randomized either to protamine administration and femoral sheath removal (group I, n = 117) or no heparin neutralization and delayed sheath removal (group II, n = 111). The hospital stay after treatment was shorter in patients receiving protamine; therefore, protamine use for neutralizing circulating heparin may be safely administered immediately after stent implantation.

Obliteration of femoral pseudoaneurysm complicating coronary intervention by direct puncture and permanent or removable coil insertion.

We report on percutaneous obliteration of femoral pseudoaneurysm complicating percutaneous coronary interventions in 6 patients. Our findings suggest that permanent or transient direct coil insertion may be an useful alternative in the treatment of pseudoaneurysm in patients who do not respond to mechanical compression.

Characterization of wet powder masses with a mixer torque rheometer. 3. Nonlinear effects of shaft speed and sample weight.

We used mixer torque rheometry to examine the effects of shaft speed and sample weight on the rheological behavior of a model wet mass consisting of microcrystalline cellulose and water. Both variables contribute differently to the measured parameters of mean torque and torque range (amplitude). For small weights, the effect of shaft speed is small, but for large weights, shaft speed has a greater effect. For large sample weights, the effect of shaft speed on measured mean torque can be modeled by the Herschel-Buckley model originally developed for concentrated dispersions, enabling yield stresses and viscosities to be calculated. The data generated compare favorably with those measured previously by capillary rheometry.

Use of the crushing strength parameter for quality control of phenobarbital-microcrystalline cellulose tablets.

Three variables of the tablet manufacturing process (duration of mixing with lubricant, maximum compression force and compression rate) were studied for their effects on various properties of direct compression phenobarbital-microcrystalline cellulose tablets. Mixing time and maximum compression force were found to have a marked influence on friability and dissolution rate; crushing strength was found to be a useful parameter for quality control.