COSMOS next generation - A public knowledge base leveraging chemical and biological data to support the regulatory assessment of chemicals.

The COSMOS Database (DB) was originally established to provide reliable data for cosmetics-related chemicals within the COSMOS Project funded as part of the SEURAT-1 Research Initiative. The database has subsequently been maintained and developed further into COSMOS Next Generation (NG), a combination of database and in silico tools, essential components of a knowledge base. COSMOS DB provided a cosmetics inventory as well as other regulatory inventories, accompanied by assessment results and in vitro and in vivo toxicity data. In addition to data content curation, much effort was dedicated to data governance - data authorisation, characterisation of quality, documentation of meta information, and control of data use. Through this effort, COSMOS DB was able to merge and fuse data of various types from different sources. Building on the previous effort, the COSMOS Minimum Inclusion (MINIS) criteria for a toxicity database were further expanded to quantify the reliability of studies. COSMOS NG features multiple fingerprints for analysing structure similarity, and new tools to calculate molecular properties and screen chemicals with endpoint-related public profilers, such as DNA and protein binders, liver alerts and genotoxic alerts. The publicly available COSMOS NG enables users to compile information and execute analyses such as category formation and read-across. This paper provides a step-by-step guided workflow for a simple read-across case, starting from a target structure and culminating in an estimation of a NOAEL confidence interval. Given its strong technical foundation, inclusion of quality-reviewed data, and provision of tools designed to facilitate communication between users, COSMOS NG is a first step towards building a toxicological knowledge hub leveraging many public data systems for chemical safety evaluation. We continue to monitor the feedback from the user community at support@mn-am.com.

In vitro and in vivo degradation profile of aliphatic polyesters subjected to electron beam sterilization.

Degradation characteristics in response to electron beam sterilization of designed and biodegradable aliphatic polyester scaffolds are relevant for clinically successful synthetic graft tissue regeneration. Scaffold degradation in vitro and in vivo were documented and correlated to the macroscopic structure and chemical design of the original polymer. The materials tested were of inherently diverse hydrophobicity and crystallinity: poly(L-lactide) (poly(LLA)) and random copolymers from L-lactide and ε-caprolactone or 1,5-dioxepan-2-one, fabricated into porous and non-porous scaffolds. After sterilization, the samples underwent hydrolysis in vitro for up to a year. In vivo, scaffolds were surgically implanted into rat calvarial defects and retrieved for analysis after 28 and 91days. In vitro, poly(L-lactide-co-1,5-dioxepan-2-one) (poly(LLA-co-DXO)) samples degraded most rapidly during hydrolysis, due to the pronounced chain-shortening reaction caused by the sterilization. This was indicated by the rapid decrease in both mass and molecular weight of poly(LLA-co-DXO). Poly(L-lactide-co-ε-caprolactone) (poly(LLA-co-CL)) samples were also strongly affected by sterilization, but mass loss was more gradual; molecular weight decreased rapidly during hydrolysis. Least affected by sterilization were the poly(LLA) samples, which subsequently showed low mass loss rate and molecular weight decrease during hydrolysis. Mechanical stability varied greatly: poly(LLA-co-CL) withstood mechanical testing for up to 182 days, while poly(LLA) and poly(LLA-co-DXO) samples quickly became too brittle. Poly(LLA-co-DXO) samples unexpectedly degraded more rapidly in vitro than in vivo. After sterilization by electron beam irradiation, the three biodegradable polymers present widely diverse degradation profiles, both in vitro and in vivo. Each exhibits the potential to be tailored to meet diverse clinical tissue engineering requirements.

Bone regeneration and stem cells.

This invited review covers research areas of central importance for orthopaedic and maxillofacial bone tissue repair, including normal fracture healing and healing problems, biomaterial scaffolds for tissue engineering, mesenchymal and foetal stem cells, effects of sex steroids on mesenchymal stem cells, use of platelet-rich plasma for tissue repair, osteogenesis and its molecular markers. A variety of cells in addition to stem cells, as well as advances in materials science to meet specific requirements for bone and soft tissue regeneration by addition of bioactive molecules, are discussed.

Understanding genetic toxicity through data mining: the process of building knowledge by integrating multiple genetic toxicity databases.

ABSTRACT Genetic toxicity data from various sources were integrated into a rigorously designed database using the ToxML schema. The public database sources include the U.S. Food and Drug Administration (FDA) submission data from approved new drug applications, food contact notifications, generally recognized as safe food ingredients, and chemicals from the NTP and CCRIS databases. The data from public sources were then combined with data from private industry according to ToxML criteria. The resulting "integrated" database, enriched in pharmaceuticals, was used for data mining analysis. Structural features describing the database were used to differentiate the chemical spaces of drugs/candidates, food ingredients, and industrial chemicals. In general, structures for drugs/candidates and food ingredients are associated with lower frequencies of mutagenicity and clastogenicity, whereas industrial chemicals as a group contain a much higher proportion of positives. Structural features were selected to analyze endpoint outcomes of the genetic toxicity studies. Although most of the well-known genotoxic carcinogenic alerts were identified, some discrepancies from the classic Ashby-Tennant alerts were observed. Using these influential features as the independent variables, the results of four types of genotoxicity studies were correlated. High Pearson correlations were found between the results of Salmonella mutagenicity and mouse lymphoma assay testing as well as those from in vitro chromosome aberration studies. This paper demonstrates the usefulness of representing a chemical by its structural features and the use of these features to profile a battery of tests rather than relying on a single toxicity test of a given chemical. This paper presents data mining/profiling methods applied in a weight-of-evidence approach to assess potential for genetic toxicity, and to guide the development of intelligent testing strategies.

Determining optimal surface roughness of TiO(2) blasted titanium implant material for attachment, proliferation and differentiation of cells derived from human mandibular alveolar bone.

In the complex process of bone formation at the implant-tissue interface, implant surface roughness is an important factor modulating osteoblastic function. In this study, primary cultures of osteoblast-like cells, derived from human mandibular bone, were used. The aim was to examine the effect of varying surface roughness of titanium implant material on cellular attachment, proliferation and differentiation. A recognized method of increasing surface roughness and enlarging the surface area of titanium implants is by blasting with titanium dioxide particles: the four specimen types in the study comprised surfaces which were machine-turned only, or blasted after turning, with 63-90 microm, 106-180 microm, or 180-300 microm TiO(2) particles, respectively. The specimens were analyzed by scanning electron microscopy and confocal laser scanning. The turned samples had the smoothest surfaces: average height deviation (S(a)) of 0.20 microm. The roughest were those blasted with 180-300 microm particles, S(a) value 1.38 microm. Blasting with intermediate particle sizes yielded S(a) values of 0.72 microm and 1.30 microm, respectively. Cell profile areas were measured using a semiautomatic interactive image analyzer. Figures were expressed as percentage of attachment. DNA synthesis was estimated by measuring the amount of [(3)H]-thymidine incorporation into trichloroacetic acid (TCA) insoluble cell precipitates. The specific activity of alkaline phosphatase was assayed using p-nitrophenylphosphate as a substrate. The ability of the cells to synthesize osteocalcin was investigated in serum-free culture medium using the ELSA-OST-NAT immunoradiometric kit. After 3 h of culture, the percentage of cellular attachment did not differ significantly between specimens blasted with 180-300 micromparticles and the turned specimens. All blasted surfaces showed significantly higher [(3)H]-thymidine incorporation than the turned surfaces (P<0.05), with the highest on the surfaces blasted with 180-300 microm particles. Osteocalcin synthesis by the cells in response to stimulation by 1,25(OH)2D3, was also significantly greater (P<0.05) on the surfaces blasted with TiO(2) particles. However, analysis of alkaline phosphatase activity disclosed no significant differences among the four surface modifications. It is concluded that in this cellular model, the proliferation and differentiation of cells derived from human mandibular bone is enhanced by surface roughness of the titanium implant. However, increasing the size of the blasting particles to 300 microm does not further increase the initial attachment of the cells compared to turned surfaces and those blasted with 63-90 microm particles.

Effects of titanium surfaces blasted with TiO2 particles on the initial attachment of cells derived from human mandibular bone. A scanning electron microscopic and histomorphometric analysis.

This study was performed to determine the effect of commercially pure titanium surfaces blasted with TiO2 particles on the biological responses of cells derived from human mandibular bone. The morphology and attachment of those cells were investigated on turned titanium surfaces (control) and surfaces blasted with 45 microns (standard), 45-63 microns, and 63-90 microns TiO2 particles. The surfaces were analyzed in a scanning electron microscope. Based on surface analyses reported elsewhere, the turned samples had the smoothest surfaces and the roughest were those blasted with the largest particles (63-90 microns). The cell profile areas were measured using a semi-automatic interactive image analyzer. The attachment was determined as a ratio of the area of cell profiles and the total micrograph area and was expressed as percentage of attachment. Morphologically, the cells were heterogeneous. In general, the cells had spread well on all titanium surfaces, indicating good attachment to both smooth and rough surfaces. After 1, 3 and 6 h, the percentage of cell attachment did not differ significantly between the surfaces blasted with 63-90 microns and the turned surfaces, but was significantly lower on the surfaces blasted with 45 microns or 45-63 microns particles. After 24 h the surfaces blasted with 63-90 microns particles had a higher rate of cell attachment than all the other surfaces including the controls. It is concluded that attachment and growth of cells originating from human mandibular bone in vitro, are influenced by the micro-texture of the implant surface.

Bonding to densely sintered alumina surfaces: effect of sandblasting and silica coating on shear bond strength of luting cements.

PURPOSE: An important determinant of the clinical success of ceramic restorations is the bond strength of the luting agent to the seating surface and the prepared tooth structures. Manufacturers of ceramic systems frequently specify both the luting agent and preluting treatment of the seating surface of the crown. Procera AllCeram is an all-ceramic crown comprising a porcelain-veneered coping of densely sintered, high-purity aluminum oxide. This study evaluated the shear bond strength of 4 luting agents: zinc-phosphate, glass-ionomer, resin-modified glass-ionomer, and resin cement (dual cured) to Procera aluminum oxide coping material. The luting agents were subjected to different surface treatments: untreated, sandblasted, or silica coated by the Rocatec system. MATERIALS AND METHODS: Cylindric and cubic specimens of the coping material were luted together, and the shear force necessary to separate the cylinder from the cube was measured with a universal testing machine. The surfaces of the specimens were also analyzed. RESULTS: No significant differences were recorded for the shear bond strengths of the luting agents to the untreated aluminum oxide. Glass-ionomer and the resin-modified glass-ionomer cements had the highest values (4.2 +/- 2.5 MPa and 4.3 +/- 1.9 MPa, respectively), and the lowest were 3.3 +/- 2.3 MPa for the resin cement and 3.2 +/- 1.0 MPa for the zinc-phosphate cement. Similar results were recorded for the sandblasted aluminum oxide surfaces, except with the glass-ionomer, which was significantly higher (12.9 +/- 2.4 MPa). For all 4 luting agents, the highest shear bond strength values were recorded for the silica-coated specimens; the highest was for the resin cement, at 36.2 +/- 7.8 MPa. CONCLUSION: The bond strengths between resin cement and aluminum oxide specimens treated by the Rocatec system were significantly higher than those of the other materials and surface treatments evaluated.

Taste buds and neuronal markers in patients with chronic renal failure.

OBJECTIVE: To study the number of taste buds and, with the use of specific markers for peripheral nervous tissue, to study the neuronal pattern in taste buds from 36 patients with chronic renal failure (CRF), 19 renal transplant recipients, and 40 healthy subjects. Of the patients with CRF, 17 patients had not started dialysis, 12 patients were on peritoneal dialysis, and 7 patients were on hemodialysis. DESIGN: From all subjects, two or three fungiform papillae were collected from the anterior part of the tongue. Cryostat sections were cut and inspected under light microscopy to determine the presence of taste buds. The sections were subsequently incubated with primary rabbit antibodies against protein gene product 9.5, substance P, and nerve growth factor receptor. RESULTS: Using these antibodies, no differences between the groups were observed. However, patients with CRF had fewer taste buds than control subjects. CONCLUSION: No immunohistochemical differences were observed between patients with CRF and healthy controls. However, patients with CRF had significantly fewer fungiform taste buds, suggesting an important factor contributing to the well-known impairment of taste acuity in this patient group.

Toxicity of formaldehyde to human oral fibroblasts and epithelial cells: influences of culture conditions and role of thiol status.

The toxicity of formaldehyde, a monomer released from certain polymeric dental materials, was studied in cultured human oral fibroblasts and epithelial cells. The influences of growth conditions were evaluated for both cell types, as well as the role of the internal and external thiol states. A one-hour exposure to formaldehyde decreased the colony-forming efficiency (CFE) of both cell types in a concentration-dependent manner, although the toxicity varied up to 100-fold with the conditions. Clearly, the presence of serum and the thiol cysteine counteracted the toxicity in fibroblasts. Similarly, pituitary extract and cysteine, or a mixture of amino acids and ethanolamines, counteracted the formaldehyde toxicity in serum-free cultures of epithelial cells. In contrast, a growth-promoting surface matrix of fibronectin and collagen did not influence the formaldehyde toxicity, as shown by both the CFE assay and a dye reduction assay. Further, a short-term change to the various growth media per se with or without the supplements serum or cysteine did not significantly alter the CFE. Analysis of the thiol state demonstrated significant differences between epithelial cells and fibroblasts, i.e., comparatively lower cellular levels of the free low-molecular-weight thiols glutathione and cysteine in fibroblasts. This result correlated to significantly higher formaldehyde toxicity in the fibroblasts than in the epithelial cells. Taken together, the results indicated the cytoprotective function of both intracellular and extracellular thiols toward formaldehyde, as well as the usefulness of thiol-free and chemically defined conditions for toxicity assessments in oral epithelial cells and fibroblasts. We conclude that the combined use of a controlled external milieu and the presumed target cell type may be advantageous in evaluations of oral toxicity mechanisms or the toxic potency of dental materials, particularly those which, like formaldehyde, may react with thiols or amines.

Five-year prospective follow-up report of the Astra Tech Dental Implant System in the treatment of edentulous mandibles.

This report of the 1st 2 prospective studies using the Astra Tech Implant System and fixed detachable bridges for rehabilitation of mandibular edentulism, presents clinical and radiographic data at the 5-year follow-up. The original material comprised 109 subjects, 56 of whom had been included in the original study, using the 1st generation Astra Tech Implant. Two subjects were excluded and the 3-year follow-up report was based on the remaining 54 subjects and 310 fixtures. After some minor changes to the fixture and the abutment, the 2nd generation Astra Tech Implant was used in 53 subjects and 308 fixtures. In all 16 subjects were lost to follow-up and the 5-year results are based on the remaining 91 subjects with 517 fixtures in function: 5 fixtures were lost due to mobility at abutment installation and during the 1st year, 2 fixtures were removed due to pain, and after 4 years in situ 1 fixture failed. As no clinical or radiographic differences were obvious in the annual registrations of the 2 studies the results have been combined. The fixed bridges were removed at 3 and 5 years to test each fixture and none was mobile. The cumulative fixture survival rate at 5 years was 98.7% and the bridge survival rate was 100%. Of the sites 82% were plaque free, and 96.8% showed no signs of inflammation. Over the 5-year period after bridge insertion, i.e. from baseline registration, there was only minor deterioration in marginal bone levels as measured on standardized intraoral radiographs: the mean differences in mm and standard deviations (SD) were -0.09 (0.27) in the 1st year, -0.20 (0.40) in the 3rd year, and -0.26 (0.53) in the 5th year. According to the stringent clinical and radiographic criteria by Albrektsson and co-workers, the successful treatment outcome and the survival rate in 91 subject over 5 years, indicates that the Astra Tech Dental Implant System with fixed detachable bridges is an appropriate method for rehabilitation of mandibular edentulism.