Cu-doped calcium phosphate supraparticles for bone tissue regeneration.

Calcium phosphate (CaP) minerals have shown great promise as bone replacement materials due to their similarity to the mineral phase of natural bone. In addition to biocompatibility and osseointegration, the prevention of infection is crucial, especially due to the high concern of antibiotic resistance. In this context, a controlled drug release as well as biodegradation are important features which depend on the porosity of CaP. An increase in porosity can be achieved by using nanoparticles (NPs), which can be processed to supraparticles, combining the properties of nano- and micromaterials. In this study, Cu-doped CaP supraparticles were prepared to improve the bone substitute properties while providing antibacterial effects. In this context, a modified sol-gel process was used for the synthesis of CaP NPs, where a Ca/P molar ratio of 1.10 resulted in the formation of crystalline ß-tricalcium phosphate (ß-TCP) after calcination at 1000 °C. In the next step, CaP NPs with Cu2+ (0.5-15.0 wt%) were processed into supraparticles by a spray drying method. Cu release experiments of the different Cu-doped CaP supraparticles demonstrated a long-term sustained release over 14 days. The antibacterial properties of the supraparticles were determined against Gram-positive (Bacillus subtilis and Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria, where complete antibacterial inhibition was achieved using a Cu concentration of 5.0 wt%. In addition, cell viability assays of the different CaP supraparticles with human telomerase-immortalized mesenchymal stromal cells (hMSC-TERT) exhibited high biocompatibility with particle concentrations of 0.01 mg mL-1 over 72 hours.

Biomimetic synthetic test system based on hydroxyapatite cement for adhesive strength evaluation of experimental mineral-organic bone adhesive materials.

The development of bone adhesive materials is a research field of high relevance for the advancement of clinical procedures. Despite this, there are currently no material candidates meeting the full range of requirements placed on such a material, such as biocompatibility, sufficient mechanical properties and bond strength under biological conditions, practical applicability in a clinical setting, and no adverse effect on the healing process itself. A serious obstacle to the advancement of the field is a lack in standardized methodology leading to comparable results between experiments and different research groups. Natural bone samples are the current gold-standard material used to perform adhesive strength experiments, however they come with a number of drawbacks, including high sample variability due to unavoidable natural causes and the impossibility to reliably recreate test conditions to repeat experiments. This paper introduces a valuable auxiliary test method capable of producing large numbers of synthetic test specimens which are chemically similar to bone and can be produced in different laboratories so to repeat experiments under constant conditions across laboratories. The substrate is based on a hydroxyapatite forming cement with addition of gelatine as organic component. Crosslinking of the organic component is performed to improve mechanical properties. In order to demonstrate the performance of the developed method, various experimental and commercial bone/tissue adhesive materials were tested and compared with results obtained by established methods to highlight the potential of the test system.

Injectable bone cement based on magnesium potassium phosphate and cross-linked alginate hydrogel designed for minimally invasive orthopedic procedures.

Bone cement based on magnesium phosphate has extremely favorable properties for its application as a bioactive bone substitute. However, further improvement is still expected due to difficult injectability and high brittleness. This paper reported the preparation of novel biocomposite cement, classified as dual-setting, obtained through ceramic hydration reaction and polymer cross-linking. Cement was composed of magnesium potassium phosphate and sodium alginate cross-linked with calcium carbonate and gluconolactone. The properties of the obtained composite material and the influence of sodium alginate modification on cement reaction were investigated. Our results indicated that proposed cements have several advantages compared to ceramic cement, like shortened curing time, diverse microstructure, increased wettability and biodegradability and improved paste cohesion and injectability. The magnesium phosphate cement with 1.50% sodium alginate obtained using a powder-to-liquid ratio of 2.5 g/mL and cross-linking ratio 90/120 of GDL/CC showed the most favorable properties, with no adverse effect on mechanical strength and osteoblasts cytocompatibility. Overall, our research suggested that this novel cement might have promising medical application prospects, especially in minimally invasive procedures.

Evaluation of baghdadite (Ca3ZrSi2O9) cements for the application as novel endodontic filling materials.

OBJECTIVES: Baghdadite (Ca3ZrSi2O9) cements of various composition have been investigated in this study regarding an application as endodontic filling materials. METHODS: Cements were either obtained by mixing mechanically activated baghdadite powder with water (maBag) or by subsequently substituting the ß-tricalcium phosphate (ß-TCP) component in a brushite forming calcium phosphate cement. The cements were analyzed for their mechanical performance, injectability, radiopacity, phase composition and antimicrobial properties. RESULTS: The cements demonstrated sufficient mechanical performance with a compressive strength of ∼1 MPa (maBag) and 2.3 - 17.4 MPa (substituted calcium phosphate cement), good injectability > 80 % depending on the powder to liquid ratio and an intrinsic radiopacity of 1.13 - 2.05 mm aluminum equivalent. Immersion in artificial saliva proved their bioactivity by the formation of calcium phosphate and calcium silicate precipitates on the cement surface. The bacterial activity of Staphylococcus aureus cultured on the surface of the cements was found to be similar compared to clinical standard ProRoot MTA cement or even reduced by a factor of 3 for Streptococcus mutans. SIGNIFICANCE: In combination with their antibacterial properties, baghdadite cements are thought to have the potential to fulfil the clinical requirements for endodontic filling materials.

Biological and mechanical performance of calcium phosphate cements modified with phytic acid.

Calcium phosphate cements, primarily brushite cements, require the addition of setting retarders to ensure adequate processing time and processability. So far, citric acid has been the primary setting retarder used in this context. Due to the poor biocompatibility, it is crucial to explore alternative options for better processing. In recent years, the setting retarder phytic acid (IP6) has been increasingly investigated. This study investigates the biological behaviour of calcium phosphate cements with varying concentrations of IP6, in addition to their physical properties. Therefore cytocompatibility in vitro testing was performed using osteoblastic (MG-63) and osteoclastic (RAW 264.7 differentiated with RANKL) cells. We could demonstrate that the physical properties like the compressive strength of specimens formed with IP6 (brushite_IP6_5 = 11.2 MPa) were improved compared to the reference (brushite = 9.8 MPa). In osteoblast and osteoclast assays, IP6 exhibited significantly better cytocompatibility in terms of cell activity and cell number for brushite cements up to 11 times compared to the brushite reference. In contrast, the calcium-deficient hydroxyapatite (CDHA) cements produced similar results for IP6 (CDHA_IP6_0.25 = 27.0 MPa) when compared to their reference (CDHA = 21.2 MPa). Interestingly, lower doses of IP6 were found to be more effective than higher doses with up to 3 times higher. Additionally, IP6 significantly increased degradation in both passive and active resorption. For these reasons, IP6 is emerging as a strong new competitor to established setting retarders such as citric acid. These cements have potential applications in bone augmentation, the stabilisation of non-load bearing fractures (craniofacial), or the cementation of metal implants.

Biological and Mechanical Performance of Dual-Setting Brushite-Silica Gel Cements.

Bone defects resulting from trauma, diseases, or surgical procedures pose significant challenges in the field of oral and maxillofacial surgery. The development of effective bone substitute materials that promote bone healing and regeneration is crucial for successful clinical outcomes. Calcium phosphate cements (CPCs) have emerged as promising candidates for bone replacement due to their biocompatibility, bioactivity, and ability to integrate with host tissues. However, there is a continuous demand for further improvements in the mechanical properties, biodegradability, and bioactivity of these materials. Dual setting of cements is one way to improve the performance of CPCs. Therefore, silicate matrices can be incorporated in these cements. Silicate-based materials have shown great potential in various biomedical applications, including tissue engineering and drug delivery systems. In the context of bone regeneration, silicate matrices offer unique advantages such as improved mechanical stability, controlled release of bioactive ions, and enhanced cellular responses. Comprehensive assessments of both the material properties and biological responses of our samples were conducted. Cytocompatibility was assessed through in vitro testing using osteoblastic (MG-63) and osteoclastic (RAW 264.7) cell lines. Cell activity on the surfaces was quantified, and scanning electron microscopy (SEM) was employed to capture images of the RAW cells. In our study, incorporation of tetraethyl orthosilicate (TEOS) in dual-curing cements significantly enhanced physical properties, attributed to increased crosslinking density and reduced pore size. Higher alkoxysilyl group concentration improved biocompatibility by facilitating greater crosslinking. Additionally, our findings suggest citrate's potential as an alternative retarder due to its positive interaction with the silicate matrix, offering insights for future dental material research. This paper aims to provide an overview of the importance of silicate matrices as modifiers for calcium phosphate cements, focusing on their impact on the mechanical properties, setting behaviour, and biocompatibility of the resulting composites.

Improving bone defect healing using magnesium phosphate granules with tailored degradation characteristics.

OBJECTIVES: Dental implant placement frequently requires preceding bone augmentation, for example, with hydroxyapatite (HA) or ß-tricalcium phosphate (ß-TCP) granules. However, HA is degraded very slowly in vivo and for ß-TCP inconsistent degradation profiles from too rapid to rather slow are reported. To shorten the healing time before implant placement, rapidly resorbing synthetic materials are of great interest. In this study, we investigated the potential of magnesium phosphates in granular form as bone replacement materials. METHODS: Spherical granules of four different materials were prepared via an emulsion process and investigated in trabecular bone defects in sheep: struvite (MgNH4PO4·6H2O), K-struvite (MgKPO4·6H2O), farringtonite (Mg3(PO4)2) and ß-TCP. RESULTS: All materials except K-struvite exhibited promising support of bone regeneration, biomechanical properties and degradation. Struvite and ß-TCP granules degraded at a similar rate, with a relative granules area of 29% and 30% of the defect area 4 months after implantation, respectively, whereas 18% was found for farringtonite. Only the K-struvite granules degraded too rapidly, with a relative granules area of 2% remaining, resulting in initial fibrous tissue formation and intermediate impairment of biomechanical properties. SIGNIFICANCE: We demonstrated that the magnesium phosphates struvite and farringtonite have a comparable or even improved degradation behavior in vivo compared to ß-TCP. This emphasizes that magnesium phosphates may be a promising alternative to established calcium phosphate bone substitute materials.

Dual-Setting Bone Cement Based On Magnesium Phosphate Modified with Glycol Methacrylate Designed for Biomedical Applications.

Magnesium phosphate cement (MPC) is a suitable alternative for the currently used calcium phosphates, owing to beneficial properties like favorable resorption rate, fast hardening, and higher compressive strength. However, due to insufficient mechanical properties and high brittleness, further improvement is still expected. In this paper, we reported the preparation of a novel type of dual-setting cement based on MPC with poly(2-hydroxyethyl methacrylate) (pHEMA). The aim of our study was to evaluate the effect of HEMA addition, especially its concentration and premix time, on the selected properties of the composite. Several beneficial effects were found: better formability, shortened setting time, and improvement of mechanical strengths. The developed cements were hardening in ∼16-21 min, consisted of well-crystallized phases and polymerized HEMA, had porosity between ∼2-11%, degraded slowly by ∼0.1-4%/18 days, their wettability was ∼20-30°, they showed compressive and bending strength between ∼45-73 and 13-20 MPa, respectively, and, finally, their Young's Modulus was close to ∼2.5-3.0 GPa. The results showed that the optimal cement composition is MPC+15%HEMA and 4 min of polymer premixing time. Overall, our research suggested that this developed cement may be used in various biomedical applications.

Experimental magnesium phosphate cement paste increases torque of trochanteric fixation nail advanced™ blades in human femoral heads.

BACKGROUND: The use of polymethylmethacrylate cement for in-situ implant augmentation has considerable disadvantages: it is potentially cytotoxic, exothermic and non-degradable. Therefore, the primary aim of this study was to develop a magnesium phosphate cement which meets the requirements for in-situ implant augmentation as an alternative. Secondly, this experimental cement was compared to commercial bone cements in a biomechanical test set-up using augmented femoral head blades. METHODS: A total of 40 human femoral heads were obtained from patients who underwent total hip arthroplasty. After bone mineral density was quantified, specimens were assigned to four treatment groups. A blade of the Trochanteric Fixation Nail Advanced™ was inserted into each specimen and augmented with either Traumacem™ V+, Paste-CPC, the experimental magnesium phosphate cement or no cement. A rotational load-to-failure-test (0° to 90°) was performed. FINDINGS: A conventional two-component magnesium phosphate cement failed in-situ implant augmentation consistently due to filter pressing. Only a glycerol-based magnesium phosphate paste was suitable for the augmentation of femoral head blades. While the blades augmented with Traumacem™ V+ yielded the highest maximum torque overall (22.1 Nm), the blades augmented with Paste-CPC and the magnesium phosphate paste also showed higher maximum torque values (15.8 and 12.8 Nm) than the control group (10.8 Nm). INTERPRETATION: This study shows for the first time the development of a degradable magnesium phosphate cement paste which fulfills the requirements for in-situ implant augmentation. Simultaneously, a 48% increase in stability is demonstrated for a scenario where implant anchorage is difficult in osteoporotic bone.

Exploring the potential of magnesium oxychloride, an amorphous magnesium phosphate, and newberyite as possible bone cement candidates.

Magnesium phosphate-based bone cements, particularly struvite (MgNH4PO4∙6H2O)-forming cements, have attracted increased scientific interest in recent years because they exhibit similar biocompatibility to hydroxyapatite while degrading much more rapidly in vivo. However, other magnesium-based minerals which might be promising are, to date, little studied. Therefore, in this study, we investigated three magnesium-based bone cements: a magnesium oxychloride cement (Mg3(OH)5Cl∙4H2O), an amorphous magnesium phosphate cement based on Mg3(PO4)2, MgO, and NaH2PO4, and a newberyite cement (MgHPO4·3H2O). Because it is not sufficiently clear from the literature to what extent these cements are suitable for clinical use, all of them were characterized and optimized regarding setting time, setting temperature, compressive strength and passive degradation in phosphate-buffered saline. Because the in vitro properties of the newberyite cement were most promising, it was orthotopically implanted into a partially weight-bearing tibial bone defect in sheep. The cement exhibited excellent biocompatibility and degraded more rapidly compared to a hydroxyapatite reference cement; after 4 months, 18% of the cement was degraded. We conclude that the newberyite cement was the most promising candidate of the investigated cements and has clear advantages over calcium phosphate cements, especially in terms of setting time and degradation behavior.

Degradation and Bone-Contact Biocompatibility of Two Drillable Magnesium Phosphate Bone Cements in an In Vivo Rabbit Bone Defect Model.

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.

Loss of zinc transporters ZIP1 and ZIP3 augments platelet reactivity in response to thrombin and accelerates thrombus formation in vivo.

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.

Ready-To-Use and Rapidly Biodegradable Magnesium Phosphate Bone Cement: In Vivo Evaluation in Sheep.

In clinical practice, hydroxyapatite (HA) cements for bone defect treatment are frequently prepared by mixing a powder component and a liquid component shortly before implantation in the operation theater, which is time-consuming and error-prone. In addition, HA cements are only slightly resorbed, that is, cement residues can still be found in the bone years after implantation. Here, these challenges are addressed by a prefabricated magnesium phosphate cement paste based on glycerol, which is ready-to-use and can be directly applied during surgery. By using a trimodal particle size distribution (PSD), the paste is readily injectable and exhibits a compressive strength of 9-14 MPa after setting. Struvite (MgNH4 PO4 ·6H2 O), dittmarite (MgNH4 PO4 ·H2 O), farringtonite (Mg3 (PO4 )2 ), and newberyite (MgHPO4 ·3H2 O) are the mineral phases present in the set cement. The paste developed here features a promising degradation of 37% after four months in an ovine implantation model, with 25% of the implant area being newly formed bone. It is concluded that the novel prefabricated paste improves application during surgery, has a suitable degradation rate, and supports bone regeneration.

Novel adhesive mineral-organic bone cements based on phosphoserine and magnesium phosphates or oxides.

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.

Solid microemulsion preconcentrates on pH responsive metal-organic framework for tableting.

Poorly water-soluble drugs are frequently formulated with lipid-based formulations including microemulsions and their preconcentrates. We detailed the solidification of drug-loaded microemulsion preconcentrates with the acid-sensitive metal-organic framework ZIF-8 by X-ray powder diffraction and solid-state nuclear magnetic resonance spectroscopy. Adsorption and desorption dynamics were analyzed by fluorescence measurement, high-performance liquid chromatography, dynamic light scattering and 1H-DOSY experiments using the model compounds Nile Red, Vitamin K1, and Lumefantrine. Preconcentrates and drugs were successfully loaded onto ZIF-8 while preserving its crystal structure. The solid powder was pressable to tablets or 3D-printed into oral dosage forms. At low pH, colloidal solutions readily formed, solubilizing the poorly water-soluble compounds. The use of stimuli-responsive metal organic frameworks as carriers for the oral delivery of lipid-based formulations points towards solid dosage forms readily forming colloidal microemulsions.

Composite grafts made of polycaprolactone fiber mats and oil-based calcium phosphate cement pastes for the reconstruction of cranial and maxillofacial defects.

OBJECTIVES: Synthetic bone substitutes which can be adapted preoperatively and patient specific may be helpful in various bony defects in the field of oral- and maxillofacial surgery. For this purpose, composite grafts made of self-setting and oil-based calcium phosphate cement (CPC) pastes, which were reinforced with 3D-printed polycaprolactone (PCL) fiber mats were manufactured. MATERIALS AND METHODS: Bone defect models were acquired using patient data from real defect situations of patients from our clinic. Using a mirror imaging technique, templates of the defect situation were fabricated via a commercially available 3D-printing system. The composite grafts were assembled layer by layer, aligned on top of these templates and fitted into the defect situation. Besides, PCL-reinforced CPC samples were evaluated regarding their structural and mechanical properties via X-ray diffraction (XRD), infrared (IR) spectroscopy, scanning electron microscopy (SEM), and 3-point-bending testing. RESULTS: The process sequence including data acquisition, template fabrication, and manufacturing of patient specific implants proved to be accurate and uncomplicated. The individual implants consisting mainly of hydroxyapatite and tetracalcium phosphate displayed good processability and a high precision of fit. The mechanical properties of the CPC cements in terms of maximum force and stress load to material fatigue were not negatively affected by the PCL fiber reinforcement, whereas clinical handling properties increased remarkably. CONCLUSION: PCL fiber reinforcement of CPC cements enables the production of very freely modelable three-dimensional implants with adequate chemical and mechanical properties for bone replacement applications. CLINICAL RELEVANCE: The complex bone morphology in the region of the facial skull often poses a great challenge for a sufficient reconstruction of bony defects. A full-fledged bone replacement here often requires the replication of filigree three-dimensional structures partly without support from the surrounding tissue. With regard to this problem, the combination of smooth 3D-printed fiber mats and oil-based CPC pastes represents a promising method for fabricating patient specific degradable implants for the treatment of various craniofacial bone defects.

Development of Neovasculature in Axially Vascularized Calcium Phosphate Cement Scaffolds.

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-1ß 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.

Calcium phosphate-based biomaterials trigger human macrophages to release extracellular traps.

As central part of the innate immune response, immune cells fight against invaders through various mechanisms, such as the release of extracellular traps (ETs). While this mechanism is mainly known for neutrophils in biomaterial contact, the release of macrophage extracellular traps (METs) in response to biomaterials has not yet been reported. An important application area for biomaterials is bone, where healing of defects of a critical size requires the implantation of grafts, which are often composed of calcium phosphates (CaPs). In this study, the response of human monocyte-derived macrophages in vitro to two different CaPs (α-tricalcium phosphate (α-TCP) and calcium deficient hydroxyapatite (CDHA)) as well as different pore structures was investigated. Scaffolds with anisotropic porosity were prepared by directional freezing, while samples with isotropic pore structure served as reference. It was revealed that ETs are released by human monocyte-derived macrophages in direct or indirect contact with CaP scaffolds. This was caused by mineral nanoparticles formed during incubation of α-TCP samples in culture medium supplemented with human platelet lysate, with an anisotropic pore structure attenuating MET formation. METs were significantly less pronounced or absent in association with CDHA samples. It was furthermore demonstrated that MET formation was accompanied by an increase in pro-inflammatory cytokines. Thus, this study provided the first evidence that macrophages are capable of releasing ETs in response to biomaterials.

Accelerated bone regeneration through rational design of magnesium phosphate cements.

Results of several studies during past years suggested that magnesium phosphate cements (MPCs) not only show excellent biocompatibility and osteoconductivity, but they also provide improved regeneration capacity due to higher solubility compared to calcium phosphates. These findings also highlighted that chemical similarity of bone substitutes to the natural bone tissue is not a determinant factor in the success of regenerative strategies. The aim of this study was to further improve the degradation speed of MPCs for a fast bone ingrowth within a few months. We confirmed our hypothesis, that decreasing the powder-liquid ratio (PLR) of cement results in an increased content of highly soluble phases such as struvite (MgNH4PO4⋅6H2O) as well as K-struvite (MgKPO4⋅6H2O). Promising compositions with a low PLR of 1 g ml-1 were implanted in partially-loaded tibia defects in sheep. Both cements were partially degraded and replaced by bone tissue after 4 months. The degradation speed of the K-struvite cement was significantly higher compared to the struvite cement, initially resulting in the formation of a cell-rich resorption zone at the surface of some implants, as determined by histology. Overall, both MPCs investigated in this study seem to be promising as an alternative to the clinically well-established, but slowly degrading calcium phosphate cements, depending on defect size and desired degradation rate. Whereas the K-struvite cement might require further modification towards a slower resorption and reduced inflammatory response in vivo, the struvite cement appears promising for the treatment of bone defects due to its continuous degradation with simultaneous new bone formation. STATEMENT OF SIGNIFICANCE: Cold setting bone cements are used for the treatment of bone defects that exceed a critical size and cannot heal on their own. They are applied pasty into the bone defect and harden afterwards so that the shape adapts to the individual defect. Magnesium phosphates such as magnesium ammonium phosphate hexahydrate (struvite) belong to a new class of these cold setting bone cements. They degrade much faster than the clinically established calcium phosphates. In this study, a magnesium phosphate that has hardly been investigated so far was implanted into partially-loaded defects in sheeps: Potassium magnesium phosphate hexahydrate. This showed even faster resorption compared to the struvite cement: after 4 months, 63% of the cement was already degraded.

Dual setting brushite-gelatin cement with increased ductility and sustained drug release.

A novel dual setting brushite-gelatin cement was achieved by genip ininitiated cross-linking of gelatin during cement setting. Although the combination of an inorganic and organic phase resulted in a decrease of the compressive strength from about 10 MPa without polymeric phase to 3-6-MPa for gelatin modified composites, an increase in elastic properties due to the gelatin hydrogel with a concentration of 10.0 w/v% was achieved. For a powder-to-liquid ratio of 2.5 g*mL-1, a shift of initial maximum stress value during compression testing was observed up to 5% deformation and tested samples showed a pseudo-ductile fracture behavior. The obtained composites of the different formulations were characterized regarding phase composition, porosity as well as drug loading capacity with rifampicin and vancomycin. For the latter, a sustained and prolonged release was realized with a drug release profile according to the Higuchi model and a release exponent of n = 0.5 for the formulation with a PLR of 2.5 g*mL-1 and an incorporation of 10.0 w/v% gelatin.