Correction: Pius et al. Effects of Aging on Osteosynthesis at Bone-Implant Interfaces. Biomolecules 2024, 14, 52.

Max L. Lee was not included as an author in the original publication [...].

Effects of Aging on Osteosynthesis at Bone-Implant Interfaces.

Joint replacement is a common surgery and is predominantly utilized for treatment of osteoarthritis in the aging population. The longevity of many of these implants depends on bony ingrowth. Here, we provide an overview of current techniques in osteogenesis (inducing bone growth onto an implant), which is affected by aging and inflammation. In this review we cover the biologic underpinnings of these processes as well as the clinical applications. Overall, aging has a significant effect at the cellular and macroscopic level that impacts osteosynthesis at bone-metal interfaces after joint arthroplasty; potential solutions include targeting prolonged inflammation, preventing microbial adhesion, and enhancing osteoinductive and osteoconductive properties.

Establishment of a femoral critical-size bone defect model in immunodeficient mice.

BACKGROUND: The development of innovative therapies for bone regeneration requires the use of advanced site-specific bone defect small-animal models. The achievement of proper fixation with a murine model is challenging due to the small dimensions of the murine femur. The aim of this investigation was to find the optimal defect size for a murine critical-size bone defect model using external fixation method. METHODS: An external fixation device was attached to the right femur of 30 mice. Femoral bone defects of 1 mm (n = 10), 2 mm (n = 10), and 3 mm (n = 10) were created. Wounds were closed without any additional treatment. To investigate bone healing during the 12-wk observation period, x-ray analysis, histomorphology, immunohistochemistry, and µCT scans were performed. RESULTS: MicroCT analyses after 12 wk showed that 3/8 1-mm defects, 5/8 2-mm defects, and 8/8 3-mm defects remained as nonunions. The defect volumes were 0.36 ± 0.42 mm³ (1-mm group), 1.40 ± 0.88 mm³ (2-mm group), and 2.88 ± 0.28 mm³ (3-mm group; P < 0.001, between all groups). CONCLUSION: Using external fixation, a defect size of 3 mm is necessary to reliably create a persisting femoral bone defect in nude mice.

Advantages and disadvantages of ceramic on ceramic total hip arthroplasty: a review.

BACKGROUND: Ceramic on ceramic (COC) total hip arthroplasty (THA) was developed to reduce wear debris and accordingly, the occurrence of osteolysis and aseptic loosening especially in younger patients. Based on the excellent tribological behavior of current COC bearings and the relatively low biological activity of ceramic particles, significant improvement in survivorship of these implants is expected. METHODS: We used manual search to identify all relevant studies reporting clinical data on COC THAs in PubMed. The objective was to determine whether current COC THA offers a better clinical outcome and survivorship than non-COC THA. RESULTS: Studies with early generation ceramic bearings yielded 68% to 84% mean survivorship at 20 years follow-up which is comparable with the survivorship of non-COC THAs. Studies on current ceramic bearings report a 10-year revision-free interval of 92% to 99%. These outcomes are comparable to the survivorship of the best non-COC THAs. However, there are still concerns regarding fracture of sandwich ceramic liners, squeaking, and impingement of the femoral neck on the rim of the ceramic liner leading to chipping, especially in younger and physically active patients. CONCLUSION: Current COC THA leads to equivalent but not improved survivorship at 10 years follow-up in comparison to the best non-COC THA. Based on this review, we recommend that surgeons weigh the potential advantages and disadvantages of current COC THA in comparison to other bearing surfaces when considering young very active patients who are candidates for THA.

Preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty.

This guideline supersedes a prior one from 2007 on a similar topic. The work group evaluated the available literature concerning various aspects of patient screening, risk factor assessment, and prophylactic treatment against venous thromboembolic disease (VTED), as well as the use of postoperative mobilization, neuraxial agents, and vena cava filters. The group recommended further assessment of patients who have had a previous venous thromboembolism but not for other potential risk factors. Patients should be assessed for known bleeding disorders, such as hemophilia, and for the presence of active liver disease. Patients who are not at elevated risk of VTED or for bleeding should receive pharmacologic prophylaxis and mechanical compressive devices for the prevention of VTED. The group did not recommend specific pharmacologic agents and/or mechanical devices. The work group recommends, by consensus opinion, early mobilization for patients following elective hip and knee arthroplasty. The use of neuraxial anesthesia can help limit blood loss but was not found to affect the occurrence of VTED. No clear evidence was established regarding whether inferior vena cava filters can prevent pulmonary embolism in patients who have a contraindication to chemoprophylaxis and/or known VTED.

Chronic inhalation exposures of Fischer 344 rats to 1,6-hexamethylene diisocyanate did not reveal a carcinogenic potential.

The polyisocyanates of 1,6-hexamethylene diisocyanate (HDI) find widespread commercial use as components of paints and in the formulation of light-stable polyurethane coating materials. This 2-year study assessed the oncogenicity of the diisocyanate monomer HDI in male and female Fischer-344 rats exposed 6 h/day, 5 days/week to mean analytical air concentrations of 0, 0.005, 0.025, and 0.164 ppm HDI. During the in-life phase, transient eye irritation was observed in 0.164 ppm males, and a slight body weight decrease (5%) in the 0.164 ppm females during the second year of exposure. There were no exposure-related effects on mortality. Compound-related, non-neoplastic histopathologic changes were limited to the respiratory tract and changes were characterized by epithelial tissue reaction to the acute irritant properties of HDI vapor. For tissues of the nasal cavity, the major histopathologic findings were degeneration of the olfactory epithelium characterized by destruction of the epithelial architecture often with narrowing or atrophy and occasional focal erosion or ulceration. In addition, there was variable degeneration of the respiratory epithelium with hyperkeratosis of the epithelium, epithelial and mucus secretory cell hyperplasia, squamous metaplasia, chronic-active inflammation, and errosive or ulcerative changes. These tissue effects along with a statistically significant decrease in body weight of female rats demonstrated attainment of a maximum tolerated dose. There was no evidence of progression of these changes in the nasal epithelium to neoplasia nor evidence of any compound-related neoplastic lesions for any of the other tissues examined. Therefore, it is concluded that HDI did not show a carcinogenic potential in this study.

Subacute inhalation exposure of rats to 1,6-hexamethylene diisocyanate with recovery period.

In this subacute inhalation toxicity study of 1,6-hexamethylene diisocyanate (HDI), groups of 10 male and 10 female Sprague-Dawley rats were exposed to 0, 0.005, 0.0175, or 0.150 ppm HDI vapor, 5 h/day, 5 days/wk for 15 exposure days and included animals sacrificed 2 wk postexposure. The purpose was to characterize the HDI-induced effects and their reversibility, and to determine a no-observed-adverse-effect level (NOAEL). No compound-related effects were found for body weights, clinical chemistry, urinalysis, hematology, and organ weights. Thus, no evidence of systemic toxicity was found in this study. The exposure-related findings were restricted to the portal of entry, the respiratory tract. Transient signs of sensory irritation were observed after the daily exposure periods, but the principal findings were the histopathologic changes of the nasal epithelium. Generally, an anterior to posterior gradient of incidence and severity was found, and the changes were characterized as acanthosis, erosion, hyperkeratosis, epithelial cell hyperplasia, chronic active inflammation, squamous metaplasia, ulceration, transitional epithelial cell degeneration, goblet-cell hyperplasia, and degeneration of the olfactory epithelium. Varying degrees of concordance between exposure concentration and incidence and/or severity of the histopathologic changes were found. During a 2-wk recovery period, a tendency toward recovery was evident for tissue changes in the nasal cavity. A NOAEL of 0.0175 ppm HDI was determined.

A 'best practices' approach to neuropathologic assessment in developmental neurotoxicity testing--for today.

A key trait of developmental neurotoxicants is their ability to cause structural lesions in the immature nervous system. Thus, neuropathologic assessment is an essential element of developmental neurotoxicity (DNT) studies that are designed to evaluate chemically-induced risk to neural substrates in young humans. The guidelines for conventional DNT assays have been established by regulatory agencies to provide a flexible scaffold for conducting such studies; recent experience has launched new efforts to update these recommendations. The present document was produced by an ad hoc subcommittee of the Society of Toxicologic Pathology (STP) tasked with examining conventional methods used in DNT neuropathology in order to define the 'best practices' for dealing with the diverse requirements of both national (EPA) and international (OECD) regulatory bodies. Recommendations (including citations for relevant neurobiological and technical references) address all aspects of the DNT neuropathology examination: study design; tissue fixation, collection, processing, and staining; qualitative and quantitative evaluation; statistical analysis; proper control materials; study documentation; and personnel training. If followed, these proposals will allow pathologists to meet the need for a sound risk assessment (balanced to address both regulatory issues and scientific considerations) in this field today while providing direction for the research needed to further refine DNT neuropathology 'best practices' in the future.

Comparison of the expression profiles induced by genotoxic and nongenotoxic carcinogens in rat liver.

Application of recently developed gene expression techniques using microarrays in toxicological studies (toxicogenomics) facilitate the interpretation of a toxic compound's mode of action and may also allow the prediction of selected toxic effects based on gene expression changes. In order to test this hypothesis, we investigated whether carcinogens at doses known to induce liver tumors in the 2-year rat bioassay deregulate characteristic sets of genes in a short term in vivo study and whether these deregulated genes represent defined biological pathways. Male Wistar rats were dosed with the four nongenotoxic hepatocarcinogens methapyrilene (MPy, 60 mg/kg/day), diethylstilbestrol (DES, 10 mg/kg/day), Wy-14643 (Wy, 60 mg/kg/day), and piperonylbutoxide (PBO, 1200 mg/kg/day). After 1, 3, 7, and 14 days, the livers were taken for histopathological evaluation and for analysis of the gene expression profiles on Affymetrix RG_U34A arrays. The expression profile of the four nongenotoxic carcinogens were compared to the profiles of the four genotoxic carcinogens 2-nitrofluorene (2-NF), dimethylnitrosamine (DMN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and aflatoxin B1 (AB1) from a similar study reported previously. By using statistical and clustering tools characteristically deregulated genes were extracted and functionally classified. Distinct cellular pathways were affected by the nongenotoxic carcinogens compared to the genotoxic carcinogens which at least partly correlated with the two-stage model of carcinogenesis. Characteristic to genotoxic carcinogens were a DNA damage response and the activation of proliferative and survival signaling. Nongenotoxic carcinogens showed responses to oxidative DNA or protein damage, as well as cell cycle progression and signs of regeneration. Many of the gene alterations found with the nongenotoxic carcinogens imply compound-specific mechanisms. Although neither a single gene nor a single pathway will be sufficient to discriminate the two classes of carcinogens, it became evident that combinations of pathway-associated gene expression profiles may be used to predict a genotoxic or nongenotoxic carcinogenic potential of a compound in short-term studies.

Characteristic expression profiles induced by genotoxic carcinogens in rat liver.

When applied in toxicological studies, the recently developed gene expression profiling techniques using microarrays, which brought forth the new field of toxicogenomics, facilitate the interpretation of a toxic compound's mechanism of action. In this study, we investigated whether genotoxic carcinogens at doses known to induce liver tumors in the 2-year rat bioassay deregulate a common set of genes in a short-term in vivo study and, if so, whether these deregulated genes represent defined biological pathways. Rats were dosed with the four genotoxic hepatocarcinogens dimethylnitrosamine (4 mg/kg/day), 2-nitrofluorene (44 mg/kg/day), aflatoxin B1 (0.24 mg/kg/day), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK, 20 mg/kg/day). After treatment for up to 14 days, the expression profiles of the livers were analyzed on Affymetrix RG_U34A microarrays. Among the significantly upregulated genes were a set of target genes of the tumor suppressor protein p53, indicating a DNA damage response. Such a response was expected and, therefore, confirmed the validity of our approach. In addition, the gene expression changes suggest a specific detoxification response, the activation of proliferative and survival signaling pathways, and some cell structural changes. These responses were strong throughout the 14 day time course for 2-nitrofluorene and aflatoxin B1; in the case of dimethylnitrosamine and NNK, the effects were weakly detectable at day 1 and then increased with time. For dimethylnitrosamine and aflatoxin B1, which caused observable inflammation in vivo, we found a corresponding upregulation of inflammatory genes at the same time points. Thus, by the toxicogenomic analysis of short-term in vivo studies, we identified genes and pathways commonly deregulated by genotoxic carcinogens, which may be indicative for the early events in tumorigenesis and, thus, predictive of later tumor development.

Revised guides for organ sampling and trimming in rats and mice--part 1.

This is the first part of a series of three articles on trimming instructions of rat and mouse protocol organs and tissues in regulatory type toxicity studies. It is based on the experience made in the European RITA and American NACAD working groups and is an extended revision of trimming guides published in 1995 (Bahnemann et al.). The optimum localization for tissue preparation, the sample size, the direction of sectioning and the number of sections to be prepared is described organ by organ. These descriptions are illustrated for each organ by a schematic drawing and a macro-photograph showing the plane of section as well as a low power view of the H&E stained slide demonstrating the optimum "end-product". This revision will improve the quality and efficiency of routine procedures and facilitate daily work in the histotechnical lab. It will promote intra- and inter-study reproducibility and comparability and thus lead to a further coherence within each study and improvement of the validity of historical control data.

The north american control animal database: a resource based on standardized nomenclature and diagnostic criteria.

Historical control data have been shown to be valuable in the interpretation and evaluation of results from rodent carcinogenicity studies. Standardization of terminology and histopathology procedures is a prerequisite for meaningful comparison of control data across studies and analysis of potential carcinogenic effects. Standardization is particularly critical for the construction of a database that includes incidence data from different studies evaluated by pathologists in different laboratories. Standardized nomenclature and diagnostic criteria have been established for neoplasms and proliferative lesions. Efforts of the National Toxicology Program, the Society of Toxicologic Pathology (STP), and the Registry of Industrial Toxicology Animal-data (RITA) have led to a harmonized pathology nomenclature for the rat and the mouse. This nomenclature with detailed descriptions of lesions is available in publications by the STP and International Agency for Research on Cancer (IARC). A listing of these terms is available on the World Wide Web. Utilizing the model established by RITA and working with the International Life Sciences Institute (ILSI), companies with laboratories in North America formed a working group in 1994 to establish and maintain a database of neoplastic and proliferative lesions from control animals in carcinogenicity studies. The rationale for development of the North American Control Animal Database (NACAD), the factors that influence tumor incidence, operation of the database, and the benefits to be realized by using a standardized approach are discussed.