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Probiotic microorganisms are used in a variety of food supplements and medical formulations to promote human health. In periodontal therapy, probiotics are mainly used in the form of gels, tablets or rinses that often tend to leak from the periodontal pocket, resulting in a strongly reduced therapeutic effect. In this pilot in vitro study, we present biodegradable alginate-based particles as an alternative, highly efficient system for a periodontal delivery of probiotic bacteria to the inflammation site. For this purpose, Lactococcus (L.) lactis was encapsulated using a standardized pump-controlled extrusion-dripping method. Time-dependent bacterial release in artificial saliva was investigated over 9 days. The effect of freeze drying was explored to ensure long-term storage of L. lactis-loaded particles. Additionally, the particles were bound to dentin surface using approved bioadhesives and subjected to shear stress in a hydrodynamic flow chamber that mimics the oral cavity in vitro. Thus, round particles within the range of 0.80-1.75 mm in radius could be produced, whereby the diameter of the dripping tip had the most significant impact on the size. Although both small and large particles demonstrated a similar release trend of L. lactis, the release rate was significantly higher in the former. Following lyophilization, particles could restore their original shape within 4 h in artificial saliva; thereby, the bacterial viability was not affected. The attachment strength to dentin intensified by an adhesive could resist forces between 10 and 25 N/m2. Full degradation of the particles was observed after 20 days in artificial saliva. Therefore, alginate particles display a valuable probiotic carrier for periodontal applications that have several crucial advantages over existing preparations: a highly stable form, prolonged continuous release of therapeutic bacteria, precise manufacturing according to required dimensions at the application site, strong attachment to the tooth with low risk of dislocation, high biocompatibility and biodegradability.
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Molecular copper catalysts have emerged as promising candidates for the electrochemical reduction of CO2 . Notable features of such systems include the ability of Cu to generate C2+ products and the well-defined active sites that allow for targeted structural tuning. However, the frequently observed in situ formation of Cu nanoclusters has undermined the advantages of the molecular frameworks. It is therefore desirable to develop Cu-based catalysts that retain their molecular structures during electrolysis. In this context, a heterogenized binuclear hydroxo-bridged phenanthroline Cu(II) compound with a short Cu···Cu distance is reported as a simple yet efficient catalyst for electrogeneration of ethylene and other C2 products. In an aqueous electrolyte, the catalyst demonstrates remarkable performance, with excellent Faradaic efficiency for C2 products (62%) and minimal H2 evolution (8%). Furthermore, it exhibits high stability, manifested by no observable degradation during 15 h of continuous electrolysis. The preservation of the atomic distribution of the active sites throughout electrolysis is substantiated through comprehensive characterizations, including X-ray photoelectron and absorption spectroscopy, scanning and transmission electron microscopy, UV-vis spectroscopy, as well as control experiments. These findings establish a solid foundation for further investigations into targeted structural tuning, opening new avenues for enhancing the catalytic performance of Cu-based molecular electrocatalysts.
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Marine sponges of the subclass Keratosa originated on our planet about 900 million years ago and represent evolutionarily ancient and hierarchically structured biological materials. One of them, proteinaceous spongin, is responsible for the formation of 3D structured fibrous skeletons and remains enigmatic with complex chemistry. The objective of this study was to investigate the interaction of spongin with iron ions in a marine environment due to biocorrosion, leading to the occurrence of lepidocrocite. For this purpose, a biomimetic approach for the development of a new lepidocrocite-containing 3D spongin scaffold under laboratory conditions at 24 °C using artificial seawater and iron is described for the first time. This method helps to obtain a new composite as "Iron-Spongin", which was characterized by infrared spectroscopy and thermogravimetry. Furthermore, sophisticated techniques such as X-ray fluorescence, microscope technique, and X-Ray diffraction were used to determine the structure. This research proposed a corresponding mechanism of lepidocrocite formation, which may be connected with the spongin amino acids functional groups. Moreover, the potential application of the biocomposite as an electrochemical dopamine sensor is proposed. The conducted research not only shows the mechanism or sensor properties of "Iron-spongin" but also opens the door to other applications of these multifunctional materials.
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Ferro , Poríferos , Animais , Biomimética , DopaminaRESUMO
Bone healing is a complex process orchestrated by various factors, such as mechanical, chemical and electrical cues. Creating synthetic biomaterials that combine several of these factors leading to tailored and controlled tissue regeneration, is the goal of scientists worldwide. Among those factors is piezoelectricity which creates a physiological electrical microenvironment that plays an important role in stimulating bone cells and fostering bone regeneration. However, only a limited number of studies have addressed the potential of combining piezoelectric biomaterials with state-of-the-art fabrication methods to fabricate tailored scaffolds for bone tissue engineering. Here, we present an approach that takes advantage of modern additive manufacturing techniques to create macroporous biomaterial scaffolds based on a piezoelectric and bioactive ceramic-crystallised glass composite. Using binder jetting, scaffolds made of barium titanate and 45S5 bioactive glass are fabricated and extensively characterised with respect to their physical and functional properties. The 3D-printed ceramic-crystallised glass composite scaffolds show both suitable mechanical strength and bioactive behaviour, as represented by the accumulation of bone-like calcium phosphate on the surface. Piezoelectric scaffolds that mimic or even surpass bone with piezoelectric constants ranging from 1 to 21 pC/N are achieved, depending on the composition of the composite. Using MC3T3-E1 osteoblast precursor cells, the scaffolds show high cytocompatibility coupled with cell attachment and proliferation, rendering the barium titanate/45S5 ceramic-crystallised glass composites promising candidates for bone tissue engineering.
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Mesenchymal stem/stromal cells (MSC) are capable of progenitor cell fraction renewal or tissue-specific differentiation. These properties are maintained during in vitro cultivation, making them an interesting model system for testing biological and pharmacological compounds. Cell cultivation in 2D is commonly used to study cellular responses, but the 2D environment does not reflect the structural situation of most cell types. Therefore, 3D culture systems have been developed to provide a more accurate physiological environment in terms of cell-cell interactions. Since knowledge about the effects of 3D culture on specific differentiation processes is limited, we studied the effects on osteogenic differentiation and the release of factors affecting bone metabolism for up to 35 days and compared them with the effects in 2D culture. We demonstrated that the selected 3D model allowed the rapid and reliable formation of spheroids that were stable over several weeks and both accelerated and enhanced osteogenic differentiation compared with the 2D culture. Thus, our experiments provide new insights into the effects of cell arrangement of MSC in 2D and 3D. However, due to the different culture dimensions, various detection methods had to be chosen, which in principle limits the explanatory power of the comparison between 2D and 3D cultures.
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(1) Background: Electrical stimulation is a promising alternative to promote bone fracture healing but with the limitation of tracking the osteogenesis progress in vivo. To overcome this issue, we present an opportunity to combine the electrical stimulation of a commercial titanium implant, which promotes osteogenesis within the fracture, with a real-time readout of the osteogenic progress by impedance sensing. This makes it possible to adjust the electrical stimulation modalities to the individual patient's fracture healing process. (2) Methods: In detail, osteogenic differentiation of several cell types was monitored under continuous or pulsatile electrical stimulation at 0.7 V AC/20 Hz for at least seven days on a titanium implant by electric cell-substrate impedance sensing (ECIS). For control, chemical induction of osteogenic differentiation was induced. (3) Results: The most significant challenge was to discriminate impedance changes caused by proliferation events from those initiated by osteogenic differentiation. This discrimination was achieved by remodeling the impedance parameter Alpha (α), which increases over time for pulsatile electrically stimulated stem cells. Boosted α-values were accompanied by an increased formation of actin stress fibers and a reduced expression of the focal adhesion kinase in the cell periphery; morphological alterations known to occur during osteogenesis. (4) Conclusions: This work provided the basis for developing an effective fracture therapy device, which can induce osteogenesis on the one hand, and would allow us to monitor the induction process on the other hand.
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A short mouse-specific peptide from zona pellucida 3 (mZP3, amino acids 328-342) has been shown to be associated with antibody-mediated contraception. In this study, we investigated the production of mZP3 in the plant, as an orally applicable host, and examined the immunogenicity of this small peptide in the BALB/c mouse model. The mZP3 peptide was inserted into the major immunodominant region of the hepatitis B core antigen and was produced in Nicotiana benthamiana plants via Agrobacterium-mediated transient expression. Soluble HBcAg-mZP3 accumulated at levels up to 2.63 mg/g leaf dry weight (LDW) containing ~172 µg/mg LDW mZP3 peptide. Sucrose gradient analysis and electron microscopy indicated the assembly of the HBcAg-mZP3 virus-like particles (VLPs) in the soluble protein fraction. Subcutaneously administered mZP3 peptide displayed on HBcAg VLPs was immunogenic in BALB/c mice at a relatively low dosage (5.5 µg mZP3 per dose) and led to the generation of mZP3-specific antibodies that bound to the native zona pellucida of wild mice. Oral delivery of dried leaves expressing HBcAg-mZP3 also elicited mZP3-specific serum IgG and mucosal IgA that cross-reacted with the zona pellucida of wild mice. According to these results, it is worthwhile to investigate the efficiency of plants producing HBcAg-mZP3 VLPs as immunogenic edible baits in reducing the fertility of wild mice through inducing antibodies that cross-react to the zona pellucida.
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HYPOTHESIS: Lateral adhesion forces are a fundamental property of liquid-solid interactions and a key aspect of dynamic droplet mobility. But, commonly applied conventional wetting analysis is limited to static and quasi-static methods and cannot resolve dynamic and spatial liquid-solid interactions. However, droplet mobility is assumed to be affected by chemical and topographic surface inhomogeneities introduced by femtosecond laser treatment. EXPERIMENTS: In this study, we used a customized droplet adhesion force instrument to determine lateral adhesion forces on various femtosecond laser-structured surface designs to obtain a deeper understanding of the dynamic droplet motion with regard to chemical and topographic surface features. FINDINGS: We show that the droplet motion was highly affected by the chemical and topographical surface design and local inhomogeneities. The droplet mobility on femtosecond laser-structured surfaces could be classified into a static, a transfer, and a kinetic regime, which is essential for designing surfaces with extreme wetting characteristics and a wide range of scientific and industrial processes. Furthermore, with proper tailoring of surface structures and chemical modification, we were able to provoke adhesion forces on self-organized laser microstructures similar to those found on the natural lotus leaves.
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Lasers , Folhas de Planta , Propriedades de Superfície , Interações Hidrofóbicas e Hidrofílicas , MolhabilidadeRESUMO
The insertion of a ureteral stent provides acute care by restoring urine flow and alleviating urinary retention or dysfunction. The problems of encrustation, bacterial colonization and biofilm formation become increasingly important when ureteral stents are left in place for a longer period of time. One way to reduce encrustation and bacterial adherence is to modify the stent surface with a diamond-like carbon coating, in combination with copper doping. The biocompatibilities of the Elastollan® base material and the a-C:H/Cu-mulitilayer coating were tested in synthetic urine. The copper content in bladder tissue was determined by atomic absorption spectroscopy and in blood and in urine by inductively coupled plasma mass spectrometry. Encrustations on the materials were analyzed by scanning electron microscopy, energy dispersive X-ray spectroscopy and Fourier transform infrared spectroscopy. A therapeutic window for copper ions of 0.5-1.0 mM was determined to kill bacteria without affecting human urothelial cells. In the rat animal model, it was found that copper release did not reach toxic concentrations in the affecting tissue of the urinary tract or in the blood. The encrustation behavior of the surfaces showed that the roughness of the amorphous carbon layer with the copper doping is probably the causal factor for the higher encrustation.
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Metallic deposition is a commonly observed phenomenon on the surface of revised femoral heads in total hip arthroplasty and can lead to increased wear due to third bodies. In order to find out the origin and composition of the transfer material, 98 retrieved femoral heads of different materials were examined with regard to the cause of revision, localization, pattern and composition of the transfer material by energy dispersive X-ray spectroscopy. We found that in 53.1%, the deposition was mostly in the region of the equator and the adjacent pole of the femoral heads. The most common cause for revision of heads with metallic deposition was polyethylene wear (43.9%). Random stripes (44.9%), random patches (41.8%) and solid patches (35.7%) were most prevalent on retrieved femoral heads. Random patches were a typical pattern in ceramic-on-ceramic bearing couples. The solid patch frequently occurred in association with dislocation of the femoral head (55%). The elemental analysis of the depositions showed a variety of different materials. In most cases, titanium was an element of the transferred material (76.5%). In addition to metallic components, several non-metallic components were also detected, such as carbon (49%) or sulfur (4.1%). Many of the determined elements could be assigned with regard to their origin with the help of the associated revision cause. Since the depositions lead to an introduction of third-body particles and thus to increased wear, the depositions on the bearing surfaces should be avoided in any case.
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BACKGROUND: Inflammation triggered by bacterial biofilms in the surrounding tissue is a major etiological factor for peri-implantitis and subsequent implant failure. However, little is known about the direct effects of bacterial corrosion and recolonization on implant failure PURPOSE: To investigate the influence of oral commensals on bacterial corrosion and recolonization of titanium surfaces. MATERIALS AND METHODS: Streptococcus sanguinis (S. sanguinis) and Porphyromonas gingivalis (P. gingivalis), which are key bacteria in oral biofilm formation, were cultured on commercially pure titanium and titanium-aluminum-vanadium (Ti6Al4V) plates in artificial saliva/brain heart infusion medium under aerobic or anaerobic conditions. Biofilm formation was examined after 7 and 21 days by crystal violet and live/dead staining. Titanium ions released into culture supernatants were analyzed over a period of 21 days by atomic absorption spectrometry. Visual changes in surface morphology were investigated using scanning electron microscopy. Biofilm formation on sterilized, biocorroded, and recolonized implant surfaces was determined by crystal violet staining. RESULTS: S. sanguinis and P. gingivalis formed stable biofilms on the titanium samples. Bacterial corrosion led to a significant increase in titanium ion release from these titanium plates (p < 0.01), which was significantly higher under aerobic conditions on pure titanium (p ≤ 0.001). No obvious morphological surface changes, such as pitting and discoloration, were detected in the titanium samples. During early biofilm formation, the addition of titanium ions significantly decreased the number of live cells. In contrast, a significant effect on biofilm mass was only detected with P. gingivalis. Bacterial corrosion had no influence on bacterial recolonization following sterilization of titanium and Ti6Al4V surfaces. CONCLUSION: Bacterial corrosion differs between oral commensal bacteria and leads to increased titanium ion release from titanium plates. The titanium ion release did not influence biofilm formation or bacterial recolonization under in vitro conditions.
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Implantes Dentários , Titânio , Ligas , Alumínio , Biofilmes , Corrosão , Implantes Dentários/microbiologia , Violeta Genciana , Porphyromonas gingivalis , Saliva Artificial , Propriedades de Superfície , Titânio/química , VanádioRESUMO
The reconstruction of critical size bone defects is still clinically challenging. Even though the transplantation of autologous bone is used as gold standard, this therapy is accompanied by donor site morbidities as well as tissue limitations. The alternatively used allografts, which are devitalized due to thermal, chemical or physical processing, often lose their matrix integrity and have diminished biomechanical properties. High Hydrostatic Pressure (HHP) may represent a gentle alternative to already existing methods since HHP treated human osteoblasts undergo cell death and HHP treated bone cylinders maintain their mechanical properties. The aim of this study was to determine the biological effects caused by HHP treatment regarding protein/matrix integrity and type of cell death in trabecular bone cylinders. Therefore, different pressure protocols (250 and 300 MPa for 10, 20 and 30 min) and end point analysis such as quantification of DNA-fragmentation, gene expression, SDS-PAGE, FESEM analysis and histological staining were performed. While both protein and matrix integrity was preserved, molecular biological methods showed an apoptotic differentiation of cell death for lower pressures and shorter applications (250 MPa for 10 and 20 min) and necrotic differentiation for higher pressures and longer applications (300 MPa for 30 min). This study serves as a basis for further investigation as it shows that HHP successfully devitalizes trabecular bone cylinders.
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Chloroplasts need to import preproteins and amino acids from the cytosol during their light-induced differentiation. Similarly, chloroplasts have to export organic matter including proteins and amino acids during leaf senescence. Members of the PRAT (preprotein and amino acid transporter) family are candidate transporters for both processes. Here, we defined the role of two small PRAT gene families, At4g26670 and At5g55510 (HP20 subfamily) versus At3g49560 and At5g24650 (HP30 subfamily) during greening of etiolated plants and during leaf senescence. Using a combination of reverse genetics, protein biochemistry and physiological tools, evidence was obtained for a role of chloroplast HP20, HP30 and HP30-2 in protein, but not amino acid, import into chloroplasts. HP20, HP30 and HP30-2 form larger complexes involved in the uptake of transit sequence-less cytosolic precursors. In addition, we identified a fraction of HP30-2 in mitochondria where it served a similar function as found for chloroplasts and operated in the uptake of transit sequence-less cytosolic precursor proteins. By contrast, HP22 was found to act in the export of proteins from chloroplasts during leaf senescence, and thus its role is entirely different from that of its orthologue, HP20. HP22 is part of a unique protein complex in the envelope of senescing chloroplasts that comprises at least 11 proteins and contains with HP65b (At5g55220) a protein that is related to the bacterial trigger factor chaperone. An ortholog of HP65b exists in the cyanobacterium Synechocystis and has previously been implicated in protein secretion. Whereas plants depleted of either HP22 or HP65b or even both were increasingly delayed in leaf senescence and retained much longer stromal chloroplast constituents than wild-type plants, HP22 overexpressors showed premature leaf senescence that was associated with accelerated losses of stromal chloroplast proteins. Together, our results identify the PRAT protein family as a unique system for importing and exporting proteins from chloroplasts.
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Understanding the rapid solidification behavior characteristics, nucleation undercooling, and nucleation mechanism is important for modifying the microstructures and properties of metal alloys. In order to investigate the rapid solidification behavior in-situ, accurate measurements of nucleation undercooling and cooling rate are required in most rapid solidification processes, e.g., in additive manufacturing (AM). In this study, differential fast scanning calorimetry (DFSC) was applied to investigate the nucleation kinetics in a single micro-sized Al-20Si (mass%) particle under a controlled cooling rate of 5000 K/s. The nucleation rates of primary Si and secondary α-Al phases were calculated by a statistical analysis of 300 identical melting/solidification experiments. Applying a model based on the classical nucleation theory (CNT) together with available thermodynamic data, two different heterogeneous nucleation mechanisms of primary Si and secondary α-Al were proposed, i.e., surface heterogeneous nucleation for primary Si and interface heterogenous nucleation for secondary α-Al. The present study introduces a practical method for a detailed investigation of rapid solidification behavior of metal particles to distinguish surface and interface nucleation.
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The design of new composite materials using extreme biomimetics is of crucial importance for bioinspired materials science. Further progress in research and application of these new materials is impossible without understanding the mechanisms of formation, as well as structural features at the molecular and nano-level. It presents a challenge to obtain a holistic understanding of the mechanisms underlying the interaction of organic and inorganic phases under conditions of harsh chemical reactions for biopolymers. Yet, an understanding of these mechanisms can lead to the development of unusual-but functional-hybrid materials. In this work, a key way of designing centimeter-scale macroporous 3D composites, using renewable marine biopolymer spongin and a model industrial solution that simulates the highly toxic copper-containing waste generated in the production of printed circuit boards worldwide, is proposed. A new spongin-atacamite composite material is developed and its structure is confirmed using neutron diffraction, X-ray diffraction, high-resolution transmission electron microscopy/selected-area electron diffraction, X-ray photoelectron spectroscopy, near-edge X-ray absorption fine structure spectroscopy, and electron paramagnetic resonance spectroscopy. The formation mechanism for this material is also proposed. This study provides experimental evidence suggesting multifunctional applicability of the designed composite in the development of 3D constructed sensors, catalysts, and antibacterial filter systems.
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Materiais Biomiméticos/química , Biopolímeros/química , Cloretos/química , Cobre/química , Nanocompostos/química , Poluição Química da Água/prevenção & controle , Amônia/química , Catálise , Humanos , Conformação Molecular , Oxirredução , Porosidade , Impressão Tridimensional , Relação Estrutura-AtividadeRESUMO
CaTiO3 is a promising candidate as a pseudo-piezoelectric scaffold material for bone implantation. In this study, pure and magnesium/iron doped CaTiO3 are synthesized by sol-gel method and spark plasma sintering. Energy dispersive X-ray mapping confirm the homogenous distribution of doping elements in sintered samples. High-energy X-ray diffraction investigations reveal that doping of nanostructured CaTiO3 increased the strain and defects in the structure of CaTiO3 compared to the pure one. This led to a stronger pseudo-piezoelectric effect in the doped samples. The charge produced in magnesium doped CaTiO3 due to the direct piezoelectric effect is (2.9 ± 0.1) pC which was larger than the one produced in pure CaTiO3 (2.1 ± 0.3) pC, whereas the maximum charge was generated by iron doped CaTiO3 with (3.6 ± 0.2) pC. Therefore, the pseudo-piezoelectric behavior can be tuned by doping. This tuning of pseudo-piezoelectric response provides the possibility to systematically study the bone response using different piezoelectric strengths and possibly adjust for bone tissue engineering.
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The demand for cardiac implantable electronic devices for arrhythmia therapy is still unabated and rising. Despite onward optimizations, lead-related problems such as infections or fractures often necessitate lead extraction. Due to adhesive thrombo-fibrotic lead encapsulations (TFLE) transvenous lead extraction is challenging and risky. However, knowledge on TFLEs and possible correlations with technical lead parameters and dwelling time (DT) were hitherto insufficiently studied. Therefore, we analyzed TFLEs of 62 lead from 35 body donor corpses to gain information for a potential lead design optimization. We examined both TFLE topography on the basis on anatomical landmarks and histo-morphological TFLE characteristics by means of histological paraffin sections and scanning electron microscopy of decellularized samples. The macroscopic analysis revealed that all leads were affected by TFLEs, mainly in the lead bearing veins. Half (47.2%) of the right-ventricular leads possessed adhesions to the tricuspid valve. On average, 49.9 ± 21.8% of the intravascular lead length was covered by TFLE of which 82.8 ± 16.2% were adhesive wall bindings (WB). The discrete TFLEs with at least one WB portion had a mean length of 95.0 ± 64.3 mm and a maximum of 200 mm. Neither sex, DT nor certain technical lead parameters showed distinct tendencies to promote or prevent TFLE. TFLE formation seems to start early in the first 1-2 weeks after implantation. The degree of fibrotization of the TFLE, starting with a thrombus, was reflected by the amount of compacted collagenous fibers and likewise largely independent from DT. TFLE thickness often reached several hundred micrometers. Calcifications were occasionally seen and appeared irregularly along the TFLE sheath. Leadless pacemaker systems have the advantage to overcome the problem with TFLEs but hold their own specific risks and limitations which are not fully known yet.
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The high biocompatibility, good mechanical properties, and perfect esthetics of ceramic dental materials motivate investigation into their suitability as an endosseous implant. Osseointegration at the interface between bone and implant surface, which is a criterion for dental implant success, is dependent on surface chemistry and topography. We found out earlier that osteoblasts on sharp-edged micro-topographies revealed an impaired cell phenotype and function and the cells attempted to phagocytize these spiky elevations in vitro. Therefore, micro-structured implants used in dental surgery should avoid any spiky topography on their surface. The sandblasted, acid-etched, and heat-treated yttria-stabilized zirconia (cer.face®14) surface was characterized by scanning electron microscopy and energy dispersive X-ray. In vitro studies with human MG-63 osteoblasts focused on cell attachment and intracellular stress level. The cer.face 14 surface featured a landscape with nano-micro hills that was most sinusoidal-shaped. The mildly curved profile proved to be a suitable material for cell anchorage. MG-63 cells on cer.face 14 showed a very low reactive oxygen species (ROS) generation similar to that on the extracellular matrix protein collagen I (Col). Intracellular adenosine triphosphate (ATP) levels were comparable to Col. Ceramic cer.face 14, with its sinusoidal-shaped surface structure, facilitates cell anchorage and prevents cell stress.
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Bioweathering mediated by microorganisms plays a significant role in biogeochemical cycles on global scales over geological timescales. Single processes induced by specific taxa have been described but could rarely be demonstrated for complex communities that dominate whole landscapes. The recently discovered grit crust of the coastal Atacama Desert, which is a transitional community between a cryptogamic ground cover and a rock-bound lithic assemblage, offers the unique chance to elucidate various bioweathering processes that occur simultaneously. Here, we present a bioweathering scenario of this biocenosis including processes such as penetration of the lithomatrix, microbial responses to wet-dry cycles, alkalinolysis, enzyme activity, and mineral re-localization. Frequently occurring fog, for example, led to a volume increase of microorganisms and the lithomatrix. This, together with pH shifts and dust accumulation, consequently results in biophysical breakdown and the formation of a terrestrial protopedon, an initial stage of pedogenesis fueled by the grit crust.
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BACKGROUND: High-molecular-weight kininogen is a cofactor of the human contact system, an inflammatory response mechanism that is activated during sepsis. It has been shown that high-molecular-weight kininogen contributes to endotoxemia, but is not critical for local host defense during pneumonia by Gram-negative bacteria. However, some important pathogens, such as Streptococcus pyogenes, can cleave kininogen by contact system activation. Whether kininogen causally affects antibacterial host defense in S. pyogenes infection, remains unknown. METHODS: Kininogen concentration was determined in course plasma samples from septic patients. mRNA expression and degradation of kininogen was determined in liver or plasma of septic mice. Kininogen was depleted in mice by treatment with selective kininogen directed antisense oligonucleotides (ASOs) or a scrambled control ASO for 3 weeks prior to infection. 24 h after infection, infection parameters were determined. FINDINGS: Data from human and mice samples indicate that kininogen is a positive acute phase protein. Lower kininogen concentration in plasma correlate with a higher APACHE II score in septic patients. We show that ASO-mediated depletion of kininogen in mice indeed restrains streptococcal spreading, reduces levels of proinflammatory cytokines such as IL-1ß and IFNγ, but increased intravascular tissue factor and fibrin deposition in kidneys of septic animals. INTERPRETATION: Mechanistically, kininogen depletion results in reduced plasma kallikrein levels and, during sepsis, in increased intravascular tissue factor that may reinforce immunothrombosis, and thus reduce streptococcal spreading. These novel findings point to an anticoagulant and profibrinolytic role of kininogens during streptococcal sepsis. FUNDING: Full details are provided in the Acknowledgements section.