@article{EwaldFuchsBoegeleinetal.2023,
  author    = {Ewald, Andrea and Fuchs, Andreas and Boegelein, Lasse and Grunz, Jan-Peter and Kneist, Karl and Gbureck, Uwe and Hoelscher-Doht, Stefanie},
  title     = {Degradation and bone-contact biocompatibility of two drillable magnesium phosphate bone cements in an in vivo rabbit bone defect model},
  series = {Materials},
  volume    = {16},
  journal   = {Materials},
  number    = {13},
  issn      = {1996-1944},
  doi       = {10.3390/ma16134650},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362824},
  year      = {2023},
  abstract  = {The use of bone-cement-enforced osteosynthesis is a growing topic in trauma surgery. In this context, drillability is a desirable feature for cements that can improve fracture stability, which most of the available cement systems lack. Therefore, in this study, we evaluated a resorbable and drillable magnesium-phosphate (MgP)-based cement paste considering degradation behavior and biocompatibility in vivo. Two different magnesium-phosphate-based cement (MPC) pastes with different amounts of phytic acid (IP 6) as setting retarder (MPC 22.5 and MPC 25) were implanted in an orthotopic defect model of the lateral femoral condyle of New Zealand white rabbits for 6 weeks. After explantation, their resorption behavior and material characteristics were evaluated by means of X-ray diffraction (XRD), porosimetry measurement, histological staining, peripheral quantitative computed tomography (pQCT), cone-beam computed tomography (CBCT) and biomechanical load-to-failure tests. Both cement pastes displayed comparable results in mechanical strength and resorption kinetics. Bone-contact biocompatibility was excellent without any signs of inflammation. Initial resorption and bone remodeling could be observed. MPC pastes with IP 6 as setting retardant have the potential to be a valuable alternative in distinct fracture patterns. Drillability, promising resorption potential and high mechanical strength confirm their suitability for use in clinical routine.},
  language  = {en}
}
@article{ElgheznawyOefteringEnglertetal.2023,
  author    = {Elgheznawy, Amro and {\"O}ftering, Patricia and Englert, Maximilian and Mott, Kristina and Kaiser, Friederike and Kusch, Charly and Gbureck, Uwe and B{\"o}sl, Michael R. and Schulze, Harald and Nieswandt, Bernhard and V{\"o}gtle, Timo and Hermanns, Heike M.},
  title     = {Loss of zinc transporters ZIP1 and ZIP3 augments platelet reactivity in response to thrombin and accelerates thrombus formation in vivo},
  series = {Frontiers in Immunology},
  volume    = {14},
  journal   = {Frontiers in Immunology},
  doi       = {10.3389/fimmu.2023.1197894},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-320154},
  year      = {2023},
  abstract  = {Zinc (Zn2+) is considered as important mediator of immune cell function, thrombosis and haemostasis. However, our understanding of the transport mechanisms that regulate Zn2+ homeostasis in platelets is limited. Zn2+ transporters, ZIPs and ZnTs, are widely expressed in eukaryotic cells. Using mice globally lacking ZIP1 and ZIP3 (ZIP1/3 DKO), our aim was to explore the potential role of these Zn2+ transporters in maintaining platelet Zn2+ homeostasis and in the regulation of platelet function. While ICP-MS measurements indicated unaltered overall Zn2+ concentrations in platelets of ZIP1/3 DKO mice, we observed a significantly increased content of FluoZin3-stainable free Zn2+, which, however, appears to be released less efficiently upon thrombin-stimulated platelet activation. On the functional level, ZIP1/3 DKO platelets exhibited a hyperactive response towards threshold concentrations of G protein-coupled receptor (GPCR) agonists, while immunoreceptor tyrosine-based activation motif (ITAM)-coupled receptor agonist signalling was unaffected. This resulted in enhanced platelet aggregation towards thrombin, bigger thrombus volume under flow ex vivo and faster in vivo thrombus formation in ZIP1/3 DKO mice. Molecularly, augmented GPCR responses were accompanied by enhanced Ca2+ and PKC, CamKII and ERK1/2 signalling. The current study thereby identifies ZIP1 and ZIP3 as important regulators for the maintenance of platelet Zn2+ homeostasis and function.},
  language  = {en}
}
@article{RennerOttoKuebleretal.2023,
  author    = {Renner, Tobias and Otto, Paul and K{\"u}bler, Alexander C. and H{\"o}lscher-Doht, Stefanie and Gbureck, Uwe},
  title     = {Novel adhesive mineral-organic bone cements based on phosphoserine and magnesium phosphates or oxides},
  series = {Journal of Materials Science: Materials in Medicine},
  volume    = {34},
  journal   = {Journal of Materials Science: Materials in Medicine},
  doi       = {10.1007/s10856-023-06714-6},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357342},
  year      = {2023},
  abstract  = {Present surgical situations require a bone adhesive which has not yet been developed for use in clinical applications. Recently, phosphoserine modified cements (PMC) based on mixtures of o-phosphoserine (OPLS) and calcium phosphates, such as tetracalcium phosphate (TTCP) or α-tricalcium phosphate (α-TCP) as well as chelate setting magnesium phosphate cements have gained increasing popularity for their use as mineral bone adhesives. Here, we investigated new mineral-organic bone cements based on phosphoserine and magnesium phosphates or oxides, which possess excellent adhesive properties. These were analyzed by X-ray diffraction, Fourier infrared spectroscopy and electron microscopy and subjected to mechanical tests to determine the bond strength to bone after ageing at physiological conditions. The novel biomineral adhesives demonstrate excellent bond strength to bone with approximately 6.6-7.3 MPa under shear load. The adhesives are also promising due to their cohesive failure pattern and ductile character. In this context, the new adhesive cements are superior to currently prevailing bone adhesives. Future efforts on bone adhesives made from phosphoserine and Mg2+ appear to be very worthwhile.},
  language  = {en}
}
@article{OuhaddiCharbonnierPorgeetal.2023,
  author    = {Ouhaddi, Yassine and Charbonnier, Baptiste and Porge, Juliette and Zhang, Yu-Ling and Garcia, Isadora and Gbureck, Uwe and Grover, Liam and Gilardino, Mirko and Harvey, Edward and Makhoul, Nicholas and Barralet, Jake},
  title     = {Development of neovasculature in axially vascularized calcium phosphate cement scaffolds},
  series = {Journal of Functional Biomaterials},
  volume    = {14},
  journal   = {Journal of Functional Biomaterials},
  number    = {2},
  issn      = {2079-4983},
  doi       = {10.3390/jfb14020105},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304026},
  year      = {2023},
  abstract  = {Augmenting the vascular supply to generate new tissues, a crucial aspect in regenerative medicine, has been challenging. Recently, our group showed that calcium phosphate can induce the formation of a functional neo-angiosome without the need for microsurgical arterial anastomosis. This was a preclinical proof of concept for biomaterial-induced luminal sprouting of large-diameter vessels. In this study, we investigated if sprouting was a general response to surgical injury or placement of an inorganic construct around the vessel. Cylindrical biocement scaffolds of differing chemistries were placed around the femoral vein. A contrast agent was used to visualize vessel ingrowth into the scaffolds. Cell populations in the scaffold were mapped using immunohistochemistry. Calcium phosphate scaffolds induced 2.7-3 times greater volume of blood vessels than calcium sulphate or magnesium phosphate scaffolds. Macrophage and vSMC populations were identified that changed spatially and temporally within the scaffold during implantation. NLRP3 inflammasome activation peaked at weeks 2 and 4 and then declined; however, IL-1β expression was sustained over the course of the experiment. IL-8, a promoter of angiogenesis, was also detected, and together, these responses suggest a role of sterile inflammation. Unexpectedly, the effect was distinct from an injury response as a result of surgical placement and also was not simply a foreign body reaction as a result of placing a rigid bioceramic next to a vein, since, while the materials tested had similar microstructures, only the calcium phosphates tested elicited an angiogenic response. This finding then reveals a potential path towards a new strategy for creating better pro-regenerative biomaterials.},
  language  = {en}
}
@article{RoedelTessmarGrolletal.2019,
  author    = {R{\"o}del, Michaela and Teßmar, J{\"o}rg and Groll, J{\"u}rgen and Gbureck, Uwe},
  title     = {Tough and Elastic alpha-Tricalcium Phosphate Cement Composites with Degradable PEG-Based Cross-Linker},
  series = {Materials},
  volume    = {12},
  journal   = {Materials},
  number    = {53},
  doi       = {10.3390/ma12010053},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226437},
  pages     = {1-20},
  year      = {2019},
  abstract  = {Dual setting cements composed of an in situ forming hydrogel and a reactive mineral phase combine high compressive strength of the cement with sufficient ductility and bending strength of the polymeric network. Previous studies were focused on the modification with non-degradable hydrogels based on 2-hydroxyethyl methacrylate (HEMA). Here, we describe the synthesis of suitable triblock degradable poly(ethylene glycol)-poly(lactide) (PEG-PLLA) cross-linker to improve the resorption capacity of such composites. A study with four different formulations was established. As reference, pure hydroxyapatite (HA) cements and composites with 40 wt\% HEMA in the liquid cement phase were produced. Furthermore, HEMA was modified with 10 wt\% of PEG-PLLA cross-linker or a test series containing only 25\% cross-linker was chosen for composites with a fully degradable polymeric phase. Hence, we developed suitable systems with increased elasticity and 5-6 times higher toughn ess values in comparison to pure inorganic cement matrix. Furthermore, conversion rate from alpha-tricalcium phosphate (alpha-TCP) to HA was still about 90\% for all composite formulations, whereas crystal size decreased. Based on this material development and advancement for a dual setting system, we managed to overcome the drawback of brittleness for pure calcium phosphate cements.},
  language  = {en}
}
@article{RoedelBaumannGrolletal.2018,
  author    = {R{\"o}del, Michaela and Baumann, Katrin and Groll, J{\"u}rgen and Gbureck, Uwe},
  title     = {Simultaneous structuring and mineralization of silk fibroin scaffolds},
  series = {Journal of Tissue Engineering},
  volume    = {9},
  journal   = {Journal of Tissue Engineering},
  doi       = {10.1177/2041731418788509},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226427},
  pages     = {1-16},
  year      = {2018},
  abstract  = {Silk fibroin is commonly used as scaffold material for tissue engineering applications. In combination with a mineralization with different calcium phosphate phases, it can also be applied as material for bone regeneration. Here, we present a study which was performed to produce mineralized silk fibroin scaffolds with controlled macroporosity. In contrast to former studies, our approach focused on a simultaneous gelation and mineralization of silk fibroin by immersion of frozen silk fibroin monoliths in acidic calcium phosphate solutions. This was achieved by thawing frozen silk fibroin monoliths in acidic calcium phosphate solution, leading to the precipitation of monocalcium phosphate within the silk fibroin matrix. In the second approach, a conversion of incorporated -tricalcium phosphate particles into brushite was successfully achieved. Furthermore, a controlled cryostructuring process of silk fibroin scaffolds was carried out leading to the formation of parallel-oriented pores with diameters of 30-50 mu m.},
  language  = {en}
}
@article{FuchsKreczyBrueckneretal.2022,
  author    = {Fuchs, Andreas and Kreczy, Dorothea and Br{\"u}ckner, Theresa and Gbureck, Uwe and Stahlhut, Philipp and Bengel, Melanie and Hoess, Andreas and Nies, Berthold and Bator, Julia and Klammert, Uwe and Linz, Christian and Ewald, Andrea},
  title     = {Bone regeneration capacity of newly developed spherical magnesium phosphate cement granules},
  series = {Clinical Oral Investigations},
  volume    = {26},
  journal   = {Clinical Oral Investigations},
  number    = {3},
  issn      = {1436-3771},
  doi       = {10.1007/s00784-021-04231-w},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-268872},
  pages     = {2619-2633},
  year      = {2022},
  abstract  = {Objectives Magnesium phosphate-based cements begin to catch more attention as bone substitute materials and especially as alternatives for the more commonly used calcium phosphates. In bone substitutes for augmentation purposes, atraumatic materials with good biocompatibility and resorbability are favorable. In the current study, we describe the in vivo testing of novel bone augmentation materials in form of spherical granules based on a calcium-doped magnesium phosphate (CaMgP) cement. Materials and Methods Granules with diameters between 500 and 710 μm were fabricated via the emulsification of CaMgP cement pastes in a lipophilic liquid. As basic material, two different CaMgP formulations were used. The obtained granules were implanted into drill hole defects at the distal femoral condyle of 27 New Zealand white rabbits for 6 and 12 weeks. After explantation, the femora were examined via X-ray diffraction analysis, histological staining, radiological examination, and EDX measurement. Results Both granule types display excellent biocompatibility without any signs of inflammation and allow for proper bone healing without the interposition of connective tissue. CaMgP granules show a fast and continuous degradation and enable fully adequate bone regeneration. Conclusions Due to their biocompatibility, their degradation behavior, and their completely spherical morphology, these CaMgP granules present a promising bone substitute material for bone augmentation procedures, especially in sensitive areas. Clinical Relevance The mostly insufficient local bone supply after tooth extractions complicates prosthetic dental restoration or makes it even impossible. Therefore, bone augmentation procedures are oftentimes inevitable. Spherical CaMgP granules may represent a valuable bone replacement material in many situations.},
  language  = {en}
}
@article{SeifertGruberGburecketal.2021,
  author    = {Seifert, Annika and Gruber, Julia and Gbureck, Uwe and Groll, J{\"u}rgen},
  title     = {Morphological control of freeze-structured scaffolds by selective temperature and material control in the ice-templating process},
  series = {Advanced Engineering Materials},
  volume    = {24},
  journal   = {Advanced Engineering Materials},
  number    = {3},
  doi       = {10.1002/adem.202100860},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-256330},
  year      = {2021},
  abstract  = {Herein, it is aimed to highlight the importance of the process parameter choice during directional solidification of polymer solutions, as they have a significant influence on the pore structure and orientation. Biopolymer solutions (alginate and chitosan) are directionally frozen, while systematically varying parameters such as the external temperature gradient, the temperature of the overall system, and the temperatures of the cooling surfaces. In addition, the effect of material properties such as molecular weight, solution concentration, or viscosity on the sample morphology is investigated. By selecting appropriate temperature gradients and cooling surface temperatures, aligned pores ranging in size between (50 ± 22) μm and (144 ± 56) μm are observed in the alginate samples, whereas the pore orientation is influenced by altering the external temperature gradient. As this gradient increases, the pores are increasingly oriented perpendicular to the sample surface. This is also observed in the chitosan samples. However, if the overall system is too cold, that is, using temperatures of the lower cooling surface down to -60 °C combined with low temperatures of the upper cooling surface, control over pore orientation is lost. This is also found when viscosity of chitosan solutions is above ≈5 Pas near the freezing point.},
  language  = {en}
}
@article{HeiligSandnerJordanetal.2021,
  author    = {Heilig, Philipp and Sandner, Phoebe and Jordan, Martin Cornelius and Jakubietz, Rafael Gregor and Meffert, Rainer Heribert and Gbureck, Uwe and Hoelscher-Doht, Stefanie},
  title     = {Experimental drillable magnesium phosphate cement is a promising alternative to conventional bone cements},
  series = {Materials},
  volume    = {14},
  journal   = {Materials},
  number    = {8},
  issn      = {1996-1944},
  doi       = {10.3390/ma14081925},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236633},
  year      = {2021},
  abstract  = {Clinically used mineral bone cements lack high strength values, absorbability and drillability. Therefore, magnesium phosphate cements have recently received increasing attention as they unify a high mechanical performance with presumed degradation in vivo. To obtain a drillable cement formulation, farringtonite (Mg\(_3\)(PO\(_4\))\(_2\)) and magnesium oxide (MgO) were modified with the setting retardant phytic acid (C\(_6\)H\(_{18}\)O\(_{24}\)P\(_6\)). In a pre-testing series, 13 different compositions of magnesium phosphate cements were analyzed concentrating on the clinical demands for application. Of these 13 composites, two cement formulations with different phytic acid content (22.5 wt\% and 25 wt\%) were identified to meet clinical demands. Both formulations were evaluated in terms of setting time, injectability, compressive strength, screw pullout tests and biomechanical tests in a clinically relevant fracture model. The cements were used as bone filler of a metaphyseal bone defect alone, and in combination with screws drilled through the cement. Both formulations achieved a setting time of 5 min 30 s and an injectability of 100\%. Compressive strength was shown to be ~12-13 MPa and the overall displacement of the reduced fracture was <2 mm with and without screws. Maximum load until reduced fracture failure was ~2600 N for the cements only and ~3800 N for the combination with screws. Two new compositions of magnesium phosphate cements revealed high strength in clinically relevant biomechanical test set-ups and add clinically desired characteristics to its strength such as injectability and drillability.},
  language  = {en}
}
@article{StuckensenLamoEspinosaMuinosLopezetal.2019,
  author    = {Stuckensen, Kai and Lamo-Espinosa, Jos{\´e} M. and Mui{\~n}os-L{\´o}pez, Emma and Ripalda-Cembor{\´a}in, Purificaci{\´o}n and L{\´o}pez-Mart{\´i}nez, Tania and Iglesias, Elena and Abizanda, Gloria and Andreu, Ion and Flandes-Iparraguirre, Mar{\´i}a and Pons-Villanueva, Juan and Elizalde, Reyes and Nickel, Joachim and Ewald, Andrea and Gbureck, Uwe and Pr{\´o}sper, Felipe and Groll, J{\"u}rgen and Granero-Molt{\´o}, Froil{\´a}n},
  title     = {Anisotropic cryostructured collagen scaffolds for efficient delivery of RhBMP-2 and enhanced bone regeneration},
  series = {Materials},
  volume    = {12},
  journal   = {Materials},
  number    = {19},
  issn      = {1996-1944},
  doi       = {10.3390/ma12193105},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-195966},
  year      = {2019},
  abstract  = {In the treatment of bone non-unions, an alternative to bone autografts is the use of bone morphogenetic proteins (BMPs), e.g., BMP-2, BMP-7, with powerful osteoinductive and osteogenic properties. In clinical settings, these osteogenic factors are applied using absorbable collagen sponges for local controlled delivery. Major side effects of this strategy are derived from the supraphysiological doses of BMPs needed, which may induce ectopic bone formation, chronic inflammation, and excessive bone resorption. In order to increase the efficiency of the delivered BMPs, we designed cryostructured collagen scaffolds functionalized with hydroxyapatite, mimicking the structure of cortical bone (aligned porosity, anisotropic) or trabecular bone (random distributed porosity, isotropic). We hypothesize that an anisotropic structure would enhance the osteoconductive properties of the scaffolds by increasing the regenerative performance of the provided rhBMP-2. In vitro, both scaffolds presented similar mechanical properties, rhBMP-2 retention and delivery capacity, as well as scaffold degradation time. In vivo, anisotropic scaffolds demonstrated better bone regeneration capabilities in a rat femoral critical-size defect model by increasing the defect bridging. In conclusion, anisotropic cryostructured collagen scaffolds improve bone regeneration by increasing the efficiency of rhBMP-2 mediated bone healing.},
  language  = {en}
}