Cluster analysis of long COVID symptoms for deciphering a syndrome and its long-term consequence.

The long-term symptoms of COVID-19 are the subject of public and scientific discussions. Understanding how those long COVID symptoms co-occur in clusters of syndromes may indicate the pathogenic mechanisms of long COVID. Our study objective was to cluster the different long COVID symptoms. We included persons who had a COVID-19 and assessed long-term symptoms (at least 4 weeks after first symptoms). Hierarchical clustering was applied to the symptoms as well as to the participants based on the Euclidean distance h of the log-values of the answers on symptom severity. The distribution of clusters within our cohort is shown in a heat map.From September 2021 to November 2023, 2371 persons with persisting long COVID symptoms participated in the study. Self-assessed long COVID symptoms were assigned to three symptom clusters. Cluster A unites rheumatological and neurological symptoms, cluster B includes neuro-psychological symptoms together with cardiorespiratory symptoms, and a third cluster C shows an association of general infection signs, dermatological and otology symptoms. A high proportion of the participants (n = 1424) showed symptoms of all three clusters. Clustering of long COVID symptoms reveals similarities to the symptomatology of already described syndromes such as the Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) or rheumatological autoinflammatory diseases. Further research may identify serological parameters or clinical risk factors associated with the shown clusters and might improve our understanding of long COVID as a systemic disease. Furthermore, multimodal treatments can be developed and scaled for symptom clusters and associated impairments.

Development of a new critical size defect model in the paranasal sinus and first approach for defect reconstruction-An in vivo maxillary bone defect study in sheep.

Fractures of the paranasal sinuses often require surgical intervention. Persisting bone defects lead to permanent visible deformities of the facial contours. Bone substitutes for reconstruction of defects with simultaneous induction of new bone formation are not commercially available for the paranasal sinus. New materials are urgently needed and have to be tested in their future area of application. For this purpose critical size defect models for the paranasal sinus have to be developed. A ≥2.4 cm large bilateral circular defect was created in the anterior wall of the maxillary sinus in six sheep via an extraoral approach. The defect was filled with two types of an osteoconductive titanium scaffold (empty scaffold vs. scaffold filled with a calcium phosphate bone cement paste) or covered with a titanium mesh either. Sheep were euthanized after four months. All animals performed well, no postoperative complications occured. Meshes and scaffolds were safely covered with soft tissue at the end of the study. The initial defect size of ≥2.4 cm only shrunk minimally during the investigation period confirming a critical size defect. No ingrowth of bone into any of the scaffolds was observed. The anterior wall of the maxillary sinus is a region with low complication rate for performing critical size defect experiments in sheep. We recommend this region for experiments with future scaffold materials whose intended use is not only limited to the paranasal sinus, as the defect is challenging even for bone graft substitutes with proven osteoconductivity. Graphical abstract.

Audiological profile of adult Long COVID patients.

INTRODUCTION: Hearing loss is one of the self-reported symptoms of Long COVID patients, however data from objective and subjective audiological tests demonstrating diminished hearing in Long COVID patients has not been published. MATERIALS AND METHODS: Respondents of a large Long COVID online survey were invited to the ENT-department for an otologic exam. The participants were split into three groups based on their history of SARS-CoV-2 infection and persistence of symptoms. Respondents with a history of a SARS-CoV-2 infection were allocated to the Long COVID group, if they reported persistent symptoms and to the Ex COVID group, if they had regained their previous level of health. Participants without a history of SARS-CoV-2 infection made up the No COVID control group. In total, 295 ears were examined with otoscopy, tympanograms, pure tone audiometry and otoacoustic emissions. Ears with known preexisting hearing loss or status post ear surgery, as well as those with abnormal otoscopic findings, non-type A tympanograms or negative Rinne test were excluded. RESULTS: Compared to the No COVID and Ex COVID groups, we did not find a clinically significant difference in either hearing thresholds or frequency specific TEOAEs. However, at 500 Hz the data from the left ear, but not the right ear showed a significantly better threshold in the Ex COVID group, compared to Long COVID and No COVID groups. Any of the other tested frequencies between 500 Hz and 8 kHz were not significantly different between the different groups. There was a significantly lower frequency-specific signal-to-noise-ratio of the TEOAEs in the Long COVID compared to the No COVID group at 2.8 kHz. At all other frequencies, there were no significant differences between the three groups in the TEOAE signal-to-noise-ratio. CONCLUSION: This study detected no evidence of persistent cochlear damage months after SARS-CoV-2 infection in a large cohort of Long COVID patients, as well as those fully recovered.

COVID-19 vaccination strategy for hospital staff in Germany: a cross-sectional study in March-April 2021.

BACKGROUND: SARS-CoV-2 vaccination for healthcare workers (HCWs) started in Germany in December 2020. Hospitals had little time to prepare a vaccination strategy. AIM: To gather information on the initial vaccination strategy for HCWs from the infection control practitioners in Germany. METHODS: A cross-sectional, ethically approved questionnaire was developed, formatted as an online survey and pre-tested. Infection control practitioners responsible for hygiene/infection prevention in 987 randomly selected German hospitals were invited to participate in the survey in March and April 2021. For statistical analysis, the hospitals were categorized into two groups based on bed capacity (<500 beds: small; ≥500 beds: large). FINDINGS: One hundred out of 987 (10%) infection control practitioners completed the survey. In 80% of the participating hospitals, HCW vaccination prioritization was based on recommendations of the German standing committee on vaccination (STIKO). Even so, only 54% prioritized the vaccination of HCWs with contact to vulnerable patients, thus deviating from STIKO recommendations. HCWs with a high personal health risk were prioritized for vaccination in 24% of the hospitals. Transferring unvaccinated HCWs to an area with less infection risk was considered by 2% of large and 12% of small hospitals. CONCLUSION: Vaccination prioritization differed across hospitals and deviated from STIKO recommendations. A pandemic preparedness concept should address the potential impact of divergent strategies compared to a common approach. In addition, further studies analysing the reasons why HCWs remain unvaccinated are needed to adopt effective strategies. This is especially important against the background of facility-based compulsory vaccination.

Infection control strategies for patients and accompanying persons during the COVID-19 pandemic in German hospitals: a cross-sectional study in March-April 2021.

BACKGROUND: Patients are at risk of nosocomial COVID-19 infection. The role of accompanying persons/visitors as potential infection donors is not yet well researched, but the risk will be influenced by prevention measures recommended by infection control practitioners. AIM: To collect information about COVID-19 infection control strategies for patients and accompanying persons from infection control practitioners in German hospitals. METHODS: A cross-sectional questionnaire was developed, ethically approved, pre-tested and formatted as an online tool. Infection control practitioners in 987 randomly selected German hospitals were invited to participate in March and April 2021. For statistical analysis, the hospitals were categorized as small (0-499 beds) or large (≥500 beds). FINDINGS: One hundred surveys were completed (response rate: 10%). A higher proportion of large (71%) than small (49%) hospitals let patients decide freely whether to wear medical or FFP2 masks. Most hospitals reported spatial separation for COVID-19 patients and non-COVID-19 cases (38%) or additionally for suspected COVID-19 cases (53%). A separation of healthcare teams for these areas existed in 54% of the hospitals. Accompaniment bans were more prevalent in large (52%) than in small hospitals (29%), but large hospitals granted more exemptions. CONCLUSION: The decision as to whether to separate areas and teams seemed to depend on the hospital's structural conditions, therefore impairing the implementation of recommendations. Accompaniment regulations differ between hospital sizes and may depend on patient numbers, case type/severity and patients' requirements. In the dynamic situation of a pandemic, it can be difficult to stay up to date with findings and recommendations on infection control.

The benefits of co-location in primary care practices: the perspectives of general practitioners and patients in 34 countries.

BACKGROUND: There is no clear evidence as to whether the co-location of primary care professionals in the same facility positively influences their way of working and the quality of healthcare as perceived by patients. The aim of this study was to identify the relationships between general practitioner (GP) co-location with other GPs and/or other professionals and the GP outcomes and patients' experiences. METHODS: We wanted to test whether GP co-location is related to a broader range of services provided, the use of clinical governance tools and inter-professional collaboration, and whether the patients of co-located GPs perceive a better quality of care in terms of accessibility, comprehensiveness and continuity of care with their GPs. The source of data was the QUALICOPC study (Quality and Costs of Primary Care in Europe), which involved surveys of GPs and their patients in 34 countries, mostly in Europe. In order to study the relationships between GP co-location and both GPs' outcomes and patients' experience, multilevel linear regression analysis was carried out. RESULTS: The GP questionnaire was filled in by 7183 GPs and the patient experience questionnaire by 61,931 patients. Being co-located with at least one other professional is the most common situation of the GPs involved in the study. Compared with single-handed GP practices, GP co-location are positively associated with the GP outcomes. Considering the patients' perspective, comprehensiveness of care has the strongest negative relationship of GP co-location of all the dimensions of patient experiences analysed. CONCLUSIONS: The paper highlights that GP mono- and multi-disciplinary co-location is related to positive outcomes at a GP level, such as a broader provision of technical procedures, increased collaboration among different providers and wider coordination with secondary care. However, GP co-location, particularly in a multidisciplinary setting, is related to less positive patient experiences, especially in countries with health systems characterised by a weak primary care structure.

Electric field-assisted formation of organically modified hydroxyapatite (ormoHAP) spheres in carboxymethylated gelatin gels.

UNLABELLED: A biomimetic strategy was developed in order to prepare organically modified hydroxyapatite (ormoHAP) with spherical shape. The technical approach is based on electric field-assisted migration of calcium ions and phosphate ions into a hydrogel composed of carboxymethylated gelatin. The electric field as well as the carboxymethylation using glucuronic acid (GlcA) significantly accelerates the mineralization process, which makes the process feasible for lab scale production of ormoHAP spheres and probably beyond. A further process was developed for gentle separation of the ormoHAP spheres from the gelatin gel without compromising the morphology of the mineral. The term ormoHAP was chosen since morphological analyses using electron microscopy (SEM, TEM) and element analysis (EDX, FT-IR, XRD) confirmed that carboxymethylated gelatin molecules use to act as organic templates for the formation of nanocrystalline HAP. The hydroxyapatite (HAP) crystals self-organize to form hollow spheres with diameters ranging from 100 to 500nm. The combination of the biocompatible chemical composition and the unique structure of the nanocomposites is considered to be a useful basis for future applications in functionalized degradable biomaterials. STATEMENT OF SIGNIFICANCE: A novel bioinspired mineralization process was developed based on electric field-assisted migration of calcium and phosphate ions into biochemically carboxymethylated gelatin acting as organic template. Advantages over conventional hydroxyapatite include particle size distribution and homogeneity as well as achievable mechanical properties of relevant composites. Moreover, specifically developed calcium ion or phosphate ion release during degradation can be useful to adjust the fate of bone cells in order to manipulate remodeling processes. The hollow structure of the spheres can be useful for embedding drugs in the core, encapsulated by the highly mineralized outer shell. In this way, controlled drug release could be achieved, which enables advanced strategies for threating bone-related diseases, e.g. osteoporosis and multiple myeloma.

[The use of benzodiazepines and Z-drugs for patients with sleeping problems - A survey among hospital doctors and nurses]. / Benzodiazepine und Z-Substanzen als Schlaf- und Beruhigungsmittel in einem Krankenhaus.

Aim | Benzodiazepines and Z-drugs are frequently prescribed sleep medications in spite of their poor risk-benefit ratio when used over a longer period of time. The aim of the study was to find out how the medical and nursing staff in a general hospital estimated the frequency of use for these drugs, and the risk-benefit ratio for elderly patients as well as the factors which positively influence the perceived use of these drugs. Methods | All members of the medical and nursing staff of a hospital received a questionnaire about their use of, and attitudes towards, benzodiazepines and Z-drugs. Absolute and relative frequencies were calculated to estimate the perceived frequency of use and the risk-benefit ratio. Multiple logistic regressions were used to analyze which factors are associated with a perceived high use of benzodiazepines or Z-drugs for insomnia. Results | More nurses than hospital doctors believed that they dispensed benzodiazepines often or always (57 % vs. 29 %) to patients with insomnia; this was also the case for Z-drugs (66 % vs. 29 %). Nearly half of the hospital doctors and 29 % of the nurses perceived more harms than benefits for benzodiazepines in the elderly. The following factors were associated with a high perceived usage of Z-drugs: working as a nurse (OR: 13,95; 95%-CI: 3,87-50,28), working in a non-surgical department (5,41; 2,00-14,61), having < 5 years of professional experience (4,90; 1,43-16,81) and feeling that the benefits of Z-drugs outweigh the risks for elderly patients (5,07; 1,48-17,35). For benzodiazepines, only the perceived positive risk-benefit ratio had an influence on the perceived use (3,35; 1,28-8.79). Conclusion | The medical and nursing staff perceived the frequency of prescription of benzodiazepines and Z-drugs and the risk-benefit ratio in different ways. Other aspects, such as working in a non-surgical department or having a smaller amount of working experience may also influence the decision to use Z-drugs.

Modulation of BK Channels by Small Endogenous Molecules and Pharmaceutical Channel Openers.

Voltage- and Ca(2+)-activated K(+) channels of big conductance (BK channels) are abundantly found in various organs and their relevance for smooth muscle tone and neuronal signaling is well documented. Dysfunction of BK channels is implicated in an array of human diseases involving many organs including the nervous, pulmonary, cardiovascular, renal, and urinary systems. In humans a single gene (KCNMA1) encodes the pore-forming α subunit (Slo1) of BK channels, but the channel properties are variable because of alternative splicing, tissue- and subcellular-specific auxiliary subunits (ß, γ), posttranslational modifications, and a multitude of endogenous signaling molecules directly affecting the channel function. Initiatives to develop drugs capable of activating BK channels (channel openers) therefore need to consider the tissue-specific variability of BK channel structure and the potential interference with endogenously produced regulatory factors. The atomic structural basis of BK channel function is only beginning to be revealed. However, building on detailed knowledge of BK channel function, including its single-channel characteristics, voltage- and Ca(2+) dependence of channel gating, and modulation by diffusible messengers, a multi-tier allosteric model of BK channel gating (Horrigan and Aldrich (HA) model) has become a valuable tool in studying modulation of the channel. Using the conceptual framework of the HA model, we here review the functional impact of endogenous modulatory factors and select small synthetic compounds that regulate BK channel activity. Furthermore, we devise experimental approaches for studying BK channel-drug interactions with the aim to classify BK-modulating substances according to their molecular mode of action.

ECM inspired coating of embroidered 3D scaffolds enhances calvaria bone regeneration.

Resorbable polymeric implants and surface coatings are an emerging technology to treat bone defects and increase bone formation. This approach is of special interest in anatomical regions like the calvaria since adults lose the capacity to heal large calvarial defects. The present study assesses the potential of extracellular matrix inspired, embroidered polycaprolactone-co-lactide (PCL) scaffolds for the treatment of 13 mm full thickness calvarial bone defects in rabbits. Moreover the influence of a collagen/chondroitin sulfate (coll I/cs) coating of PCL scaffolds was evaluated. Defect areas filled with autologous bone and empty defects served as reference. The healing process was monitored over 6 months by combining a novel ultrasonographic method, radiographic imaging, biomechanical testing, and histology. The PCL coll I/cs treated group reached 68% new bone volume compared to the autologous group (100%) and the biomechanical stability of the defect area was similar to that of the gold standard. Histological investigations revealed a significantly more homogenous bone distribution over the whole defect area in the PCL coll I/cs group compared to the noncoated group. The bioactive, coll I/cs coated, highly porous, 3-dimensional PCL scaffold acted as a guide rail for new skull bone formation along and into the implant.

Cholinergic nerve fibers in bone defects of a rat osteoporosis model and their regulation by implantation of bone substitution materials.

OBJECTIVES: Bone is innervated by autonomic nervous system that consists of sympathetic and parasympathetic nerves that were recently identified in bone. Thus we asked whether parasympathetic nerves occur in bone defects and at the interface of substitution materials that were implanted for stabilization and improvement of healing in an osteoporosis animal model. METHODS: Osteoporosis was induced in rats by ovariectomy and deficiency diet. A wedge-shaped osteotomy was performed in the metaphyseal area of femur. Eight different implants were inserted that were based on calcium phosphate cement, iron, silica-mineralized collagen, and modifications with strontium. Nerves were identified by immunohistochemistry with antibodies against vesicular acetylcholine transporter (VAChT), tyrosine hydroxylase (TH) and protein gene product 9.5 (PGP 9.5) as neuronal marker. RESULTS: Cholinergic nerves identified with VAChT immunostaining were detected in defects filled with granulation tissue and in surrounding mast cells. No immunolabeling of cholinergic nerves was found after implantation. The general presence of nerves was reduced after implantation as shown by PGP 9.5. Sympathetic nerves identified by TH immunolabeling were increased in strontium functionalized materials. CONCLUSION: Since cholinergic innervation was diminished after implantation a further increase in the compatibility of substitution materials to nerves could improve defect healing especially in osteoporotic bone.

Artificial extracellular matrices of collagen and sulphated hyaluronan enhance the differentiation of human mesenchymal stem cells in the presence of dexamethasone.

In this study we investigated the potential of artificial extracellular matrix (aECM) coatings containing collagen II and two types of glycosaminoglycan (GAGs) with different degrees of sulphation to promote human bone formation in biomedical applications. To this end their impact on growth and osteogenic differentiation of human mesenchymal stem cells (hMSCs) was assessed. The cell proliferation was found to be significantly retarded in the first 14 days of culture on surfaces coated with collagen II and GAGs (coll-II/GAG) as compared to tissue culture polystyrol (TCPS) and those coated with collagen II. At later time points it only tended to be retarded on coll-II/sHya3.1. Heat-inactivation of the serum significantly reduced cell numbers on collagen II and coll-II/sHya3.1. Alkaline phosphatase (ALP) activity and calcium deposition, on the other hand, were higher for coatings containing sHya3.1 and were not significantly changed by heat-inactivation of the serum. Expression levels of the bone matrix proteins bone sialoprotein (BSP-II) and osteopontin (OP) were also increased on aECM coatings as compared to TCPS, which further validated the differentiation of hMSCs towards the osteogenic lineage. These observations reveal that aECM coatings, in particular those containing sHya3.1, are suitable to promote the osteogenic differentiation of hMSCs.

Properties of injectable ready-to-use calcium phosphate cement based on water-immiscible liquid.

Calcium phosphate cements (CPCs) are highly valuable materials for filling bone defects and bone augmentation by minimal invasive application via percutaneous injection. In the present study some key features were significantly improved by developing a novel injectable ready-to-use calcium phosphate cement based on water-immiscible carrier liquids. A combination of two surfactants was identified to facilitate the targeted discontinuous exchange of the liquid for water after contact with aqueous solutions, enabling the setting reaction to take place at distinct ratios of cement components to water. This prolonged the shelf life of the pre-mixed paste and enhanced reproducibility during application and setting reactions. The developed paste technology is applicable for different CPC formulations. Evaluations were performed for the formulation of an α-TCP-based CPC as a representative example for the preparation of injectable pastes with a powder-to-carrier liquid ratio of up to 85:15. We demonstrate that the resulting material retains the desirable properties of conventional CPC counterparts for fast setting, mechanical strength and biocompatibility, shows improved cohesion and will most probably show a similar degree of resorbability due to identical mineral structure of the set products.

Calcium phosphate phases integrated in silica/collagen nanocomposite xerogels enhance the bioactivity and ultimately manipulate the osteoblast/osteoclast ratio in a human co-culture model.

A human co-culture model of osteoblasts and osteoclasts, derived from bone marrow stromal cells and monocytes respectively, was used to characterize the influence of biomaterial modification on the bioactivity and ultimately the ratio of bone-forming to bone-resorbing cells cultivated directly on the surface. Nanocomposites of silica and collagen have been shown to function as skeletal structures in nature and were reproduced in vitro by using a sol-gel approach. The resulting xerogels exhibit a number of features that make it a valuable system for the development of innovative materials for bone substitution applications. In the present study, the incorporation of different calcium phosphate phases in silica/collagen-based gels was demonstrated to enhance the bioactivity of these samples. This ability of the biomaterial to precipitate calcium phosphate on the surface when incubated in simulated body fluids or cell culture medium is generally considered to an advantageous property for bone substitution materials. By co-cultivating human osteoblasts and osteoclasts up to 42 days on the xerogels, we demonstrate that the long-term ratio of these cell types depends on the level of bioactivity of the substrate samples. Biphasic silica/collagen xerogels exhibited comparably low bioactivity but encouraged proliferation of osteoblasts in comparison to osteoclast formation. A balanced ratio of both cell types was detected for moderately bioactive triphasic xerogels with 5% calcium phosphate. However, enhancing the bioactivity of the xerogel samples by increasing the calcium phosphate phase percentage to 20% resulted in a diminished number of osteoblasts in favor of osteoclast formation. Quantitative evaluation was carried out by biochemical methods (calcium, DNA, ALP, TRAP 5b) as well as RT-PCR (ALP, BSP II, OC, RANKL, TRAP, CALCR, VTNR, CTSK), and was supported by confocal laser scanning microscopy (cell nuclei, actin, CD68, TRAP) as well as scanning electron microscopy.

A flexible microrobotic platform for handling microscale specimens of fibrous materials for microscopic studies.

One of the most challenging issues faced in handling specimens for microscopy, is avoiding artefacts and structural changes in the samples caused by human errors. In addition, specimen handling is a laborious and time-consuming task and requires skilful and experienced personnel. This paper introduces a flexible microrobotic platform for the handling of microscale specimens of fibrous materials for various microscopic studies such as scanning electron microscopy and nanotomography. The platform is capable of handling various fibres with diameters ranging from 10 to 1000 µm and lengths of 100 µm-15 mm, and mounting them on different types of specimen holders without damaging them. This tele-operated microrobotic platform minimizes human interaction with the samples, which is one of the main sources contributory to introducing artefacts into the specimens. The platform also grants a higher throughput and an improved success rate of specimen handling, when compared to the manual processes. The operator does not need extensive experience of microscale manipulation and only a short training period is sufficient to operate the platform. The requirement of easy configurability for various samples and sample holders is typical in the research and development of materials in this field. Therefore, one of the main criteria for the design of the microrobotic platform was the ability to adapt the platform to different specimen handling methods required for microscopic studies. To demonstrate this, three experiments are carried out using the microrobotic platform. In the first experiment, individual paper fibres are mounted successfully on scanning electron microscopy specimen holders for the in situ scanning electron microscopy diagonal compression test of paper fibres. The performance of the microrobotic platform is compared with a skilled laboratory worker performing the same experiment. In the second experiment, a strand of human hair and an individual paper fibre bond are mounted on a specimen holder for nanotomography studies. In the third experiment, individual paper fibre bonds with controlled crossing and vertical angles are made using the microrobotic platform. If an industrial application requires less flexibility but a higher speed when handling one type of sample to a specific holder, then the platform can be automated in the future.

Effect of silica and hydroxyapatite mineralization on the mechanical properties and the biocompatibility of nanocomposite collagen scaffolds.

A recently established materials concept of biomimetic composites based on silica, collagen, and calcium phosphates was adapted for the preparation of porous scaffolds suitable for tissue engineering applications. Mineralization was achieved by directed nucleation of silica on the templating organic phase during a sol-gel process with or without addition of hydroxyapatite. Both mineral phases (25 wt %, individually or combined in equal shares) influenced the scaffold's morphology at the nanoscale. Enhancement of apparent density and compressive strength was similar for silica or hydroxyapatite mineralization; however the stiffening effect of hydroxyapatite was much higher. All scaffold modifications provided proper conditions for adhesion, proliferation, and osteogenic differentiation of human bone marrow stromal cells. The open porosity allowed cells to migrate throughout the scaffolds while maintaining their viability, both confirmed by MTT staining and confocal laser scanning microscopy. Initial cell distributions were graduated due to collagen mineralization, but balanced out over the cultivation time of 28 days. RT-PCR analyses revealed higher gene expression of ALP but lower expression of BSP II and osteocalcin because of collagen mineralization. The results demonstrate that both silica and hydroxyapatite offer comparable possibilities to tailor mechanical properties of collagen-based scaffolds without being detrimental to in vitro biocompatibility.

Diffractive optical elements utilized for efficiency enhancement of photovoltaic modules.

Common solar cells used in photovoltaic modules feature metallic contacts which partially block the sunlight from reaching the semiconductor layer and reduce the overall efficiency of the modules. Diffractive optical elements were generated in the bulk glass of a photovoltaic module by ultrafast laser irradiation to direct light away from the contacts. Calculations of the planar electromagnetic wave diffraction and propagation were performed using the rigorous coupled wave analysis technique providing quantitative estimations for the potential efficiency enhancement of photovoltaic modules.

[Resorbable bone substitution materials: An overview of commercially available materials and new approaches in the field of composites]. / Resorbierbare Knochenersatzmaterialien: Eine Übersicht kommerziell verfügbarer Werkstoffe und neuer Forschungsansätze auf dem Gebiet der Komposite.

When acquired or inborn bony defects cannot heal by the natural regeneration process due to being above the critical size or to particular diseases, e.g. osteoporosis, it becomes necessary to use bone substitute materials. These are materials which replace the missing bone tissue in host tissue and stimulate the bone healing process by mechanical and structural support either alone or in combination with other substances. This supporting effect can be attended by natural as well as artificial bone substitute materials and in a variety of ways. The biological efficiency of a bone substitute material is often classified with respect to the terms osteogenic, osteoconductive and osteoinductive stimulation. In reality however there is an overlap of several effective principles. Due to the limited availability of autologous bone and the disadvantages for the patient associated with the removal, intensive research is being carried out into artificial alternatives. The present article aims to offer some orientation in this confusing field by a systematic description of the various bone substitute materials.

Development of an osteoblast/osteoclast co-culture derived by human bone marrow stromal cells and human monocytes for biomaterials testing.

The communication of bone-forming osteoblasts and bone-resorbing osteoclasts is a fundamental requirement for balanced bone remodelling. For biomaterial research, development of in vitro models is necessary to investigate this communication. In the present study human bone marrow stromal cells and human monocytes were cultivated in order to differentiate into osteoblasts and osteoclasts, respectively. Finally, a cultivation regime was identified which firstly induces the differentiation of the human bone marrow stromal cells followed by the induction of osteoclastogenesis through the osteoblasts formed--without the external addition of the factors RANKL and M-CSF. As a feedback on osteoblasts enhanced gene expression of BSP II was detected for modifications which facilitated the formation of large multinuclear osteoclasts. Phenotype characterization was performed by biochemical methods (DNA, LDH, ALP, TRAP 5b), gene expression analysis (ALP, BSP II, RANKL, IL-6, VTNR, CTSK, TRAP, OSCAR, CALCR) as well as light microscopy, confocal laser scanning microscopy, and scanning electron microscopy. After establishing this model on polystyrene, similar positive results were obtained for cultivation on a relevant bone substitution material--a composite xerogel of silica, collagen, and calcium phosphate.

Altered activity-rest patterns in mice with a human autosomal-dominant nocturnal frontal lobe epilepsy mutation in the ß2 nicotinic receptor.

High-affinity nicotinic receptors containing ß2 subunits (ß2*) are widely expressed in the brain, modulating many neuronal processes and contributing to neuropathologies such as Alzheimer's disease, Parkinson's disease and epilepsy. Mutations in both the α4 and ß2 subunits are associated with a rare partial epilepsy, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). In this study, we introduced one such human missense mutation into the mouse genome to generate a knock-in strain carrying a valine-to-leucine mutation ß2V287L. ß2(V287L) mice were viable and born at an expected Mendelian ratio. Surprisingly, mice did not show an overt seizure phenotype; however, homozygous mice did show significant alterations in their activity-rest patterns. This was manifest as an increase in activity during the light cycle suggestive of disturbances in the normal sleep patterns of mice; a parallel phenotype to that found in human ADNFLE patients. Consistent with the role of nicotinic receptors in reward pathways, we found that ß2(V287L) mice did not develop a normal proclivity to voluntary wheel running, a model for natural reward. Anxiety-related behaviors were also affected by the V287L mutation. Mutant mice spent more time in the open arms on the elevated plus maze suggesting that they had reduced levels of anxiety. Together, these findings emphasize several important roles of ß2* nicotinic receptors in complex biological processes including the activity-rest cycle, natural reward and anxiety.