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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.
Brushite cements have been clinically used for irregular bone defect filling applications, and various strategies have been previously reported to modify and improve their physicochemical properties such as strength and injectability. However, strategies to address other limitations of brushite cements such as low radiopacity or acidity without negatively impacting mechanical strength have not yet been reported. In this study, we report the effect of substituting the beta-tricalcium phosphate reactant in brushite cement with baghdadite (Ca\(_3\)ZrSi\(_2\)O\(_9\)), a bioactive zirconium-doped calcium silicate ceramic, at various concentrations (0, 5, 10, 20, 30, 50, and 100 wt%) on the properties of the final brushite cement product. X-ray diffraction profiles indicate the dissolution of baghdadite during the cement reaction, without affecting the crystal structure of the precipitated brushite. EDX analysis shows that calcium is homogeneously distributed within the cement matrix, while zirconium and silicon form cluster-like aggregates with sizes ranging from few microns to more than 50 µm. X-ray images and µ-CT analysis indicate enhanced radiopacity with increased incorporation of baghdadite into brushite cement, with nearly a doubling of the aluminium equivalent thickness at 50 wt% baghdadite substitution. At the same time, compressive strength of brushite cement increased from 12.9 ± 3.1 MPa to 21.1 ± 4.1 MPa with 10 wt% baghdadite substitution. Culture medium conditioned with powdered brushite cement approached closer to physiological pH values when the cement is incorporated with increasing amounts of baghdadite (pH = 6.47 for pure brushite, pH = 7.02 for brushite with 20 wt% baghdadite substitution). Baghdadite substitution also influenced the ionic content in the culture medium, and subsequently affected the proliferative activity of primary human osteoblasts in vitro. This study indicates that baghdadite is a beneficial additive to enhance the radiopacity, mechanical performance and cytocompatibility of brushite cement
Dicalcium phosphate cement preparation requires the addition of setting retarders to meet clinical requirements regarding handling time and processability. Previous studies have focused on the influence of different setting modifiers on material properties such as mechanical performance or injectability, while ignoring their influence on biological cement properties as they are used in low concentrations in the cement pastes and the occurrence of most compounds in human tissues. Here, analyses of both material and biological behavior were carried out on samples with common setting retardants (citric acid, sodium pyrophosphate, sulfuric acid) and novel (phytic acid). Cytocompatibility was evaluated by in vitro tests with osteoblastic (hFOB 1.19) and osteoclastic (RAW 264.7) cells. We found cytocompatibility was better for sodium pyrophosphate and phytic acid with a three-fold cell metabolic activity by WST-1 test, whereas samples set with citric acid showed reduced cell number as well as cell activity. The compressive strength (CS) of cements formed with phytic acid (CS = 13 MPa) were nearly equal to those formed with citric acid (CS = 15 MPa) and approximately threefold higher than for other setting retardants. Due to a proven cytocompatibility and high mechanical strength, phytic acid seems to be a candidate replacement setting retardant for dicalcium phosphate cements.
In this study, the hydraulic reactivity and cement formation of baghdadite (Ca\(_{3}\)ZrSi\(_{2}\)O\(_{9}\)) was investigated. The material was synthesized by sintering a mixture of CaCO\(_{3}\), SiO\(_{2}\), and ZrO\(_{2}\) and then mechanically activated using a planetary mill. This leads to a decrease in particle and crystallite size and a partial amorphization of baghdadite as shown by X-ray powder diffraction (XRD) and laser diffraction measurements. Baghdadite cements were formed by the addition of water at a powder to liquid ratio of 2.0 g/ml. Maximum compressive strengths were found to be ~2 MPa after 3-day setting for a 24-h ground material. Inductively coupled plasma mass spectrometry (ICP-MS) measurements showed an incongruent dissolution profile of set cements with a preferred dissolution of calcium and only marginal release of zirconium ions. Cement formation occurs under alkaline conditions, whereas the unground raw powder leads to a pH of 11.9 during setting, while prolonged grinding increased pH values to approximately 12.3.
Background:
Recent studies have shown that human ferritin can be used as a reporter of gene expression for magnetic resonance imaging (MRI). Bacteria also encode three classes of ferritin-type molecules with iron accumulation properties.
Methods and Findings:
Here, we investigated whether these bacterial ferritins can also be used as MRI reporter genes and which of the bacterial ferritins is the most suitable reporter. Bacterial ferritins were overexpressed in probiotic E. coli Nissle 1917. Cultures of these bacteria were analyzed and those generating highest MRI contrast were further investigated in tumor bearing mice. Among members of three classes of bacterial ferritin tested, bacterioferritin showed the most promise as a reporter gene. Although all three proteins accumulated similar amounts of iron when overexpressed individually, bacterioferritin showed the highest contrast change. By site-directed mutagenesis we also show that the heme iron, a unique part of the bacterioferritin molecule, is not critical for MRI contrast change. Tumor-specific induction of bacterioferritin-expression in colonized tumors resulted in contrast changes within the bacteria-colonized tumors.
Conclusions:
Our data suggest that colonization and gene expression by live vectors expressing bacterioferritin can be monitored by MRI due to contrast changes.
Bone graft substitutes in orthopedic applications have to fulfill various demanding requirements. Most calcium phosphate (CaP) bone graft substitutes are highly porous to achieve bone regeneration, but typically lack mechanical stability. This study presents a novel approach, in which a scaffold structure with appropriate properties for bone regeneration emerges from the space between specifically shaped granules. The granule types were tetrapods (TEPO) and pyramids (PYRA), which were compared to porous CaP granules (CALC) and morselized bone chips (BC). Bulk materials of the granules were mechanically loaded with a peak pressure of 4 MP; i.e., comparable to the load occurring behind an acetabular cup. Mechanical loading reduced the volume of CALC and BC considerably (89% and 85%, respectively), indicating a collapse of the macroporous structure. Volumes of TEPO and PYRA remained almost constant (94% and 98%, respectively). After loading, the porosity was highest for BC (46%), lowest for CALC (25%) and comparable for TEPO and PYRA (37%). The pore spaces of TEPO and PYRA were highly interconnected in a way that a virtual object with a diameter of 150 µm could access 34% of the TEPO volume and 36% of the PYRA volume. This study shows that a bulk of dense CaP granules in form of tetrapods and pyramids can create a scaffold structure with load capacities suitable for the regeneration of an acetabular bone defect
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.
This study aimed to develop printable calcium magnesium phosphate pastes that harden by immersion in ammonium phosphate solution post-printing. Besides the main mineral compound, biocompatible ceramic, magnesium oxide and hydroxypropylmethylcellulose (HPMC) were the crucial components. Two pastes with different powder to liquid ratios of 1.35 g/mL and 1.93 g/mL were characterized regarding their rheological properties. Here, ageing over the course of 24 h showed an increase in viscosity and extrusion force, which was attributed to structural changes in HPMC as well as the formation of magnesium hydroxide by hydration of MgO. The pastes enabled printing of porous scaffolds with good dimensional stability and enabled a setting reaction to struvite when immersed in ammonium phosphate solution. Mechanical performance under compression was approx. 8–20 MPa as a monolithic structure and 1.6–3.0 MPa for printed macroporous scaffolds, depending on parameters such as powder to liquid ratio, ageing time, strand thickness and distance.
Calcium phosphate biocements based on calcium phosphate chemistry are well-established biomaterials for the repair of non-load bearing bone defects due to the brittle nature and low flexural strength of such cements. This article features reinforcement strategies of biocements based on various intrinsic or extrinsic material modifications to improve their strength and toughness. Altering particle size distribution in conjunction with using liquefiers reduces the amount of cement liquid necessary for cement paste preparation. This in turn decreases cement porosity and increases the mechanical performance, but does not change the brittle nature of the cements. The use of fibers may lead to a reinforcement of the matrix with a toughness increase of up to two orders of magnitude, but restricts at the same time cement injection for minimal invasive application techniques. A novel promising approach is the concept of dual-setting cements, in which a second hydrogel phase is simultaneously formed during setting, leading to more ductile cement-hydrogel composites with largely unaffected application properties.
Background
The role of cement-augmented screw fixation for calcaneal fracture treatment remains unclear. Therefore, this study was performed to biomechanically analyze screw osteosynthesis by reinforcement with either a calcium phosphate (CP)-based or polymethylmethacrylate (PMMA)-based injectable bone cement.
Methods
A calcaneal fracture (Sanders type IIA) including a central cancellous bone defect was generated in 27 synthetic bones, and the specimens were assigned to 3 groups. The first group was fixed with four screws (3.5 mm and 6.5 mm), the second group with screws and CP-based cement (Graftys (R) QuickSet; Graftys, Aix-en-Provence, France), and the third group with screws and PMMA-based cement (Traumacem (TM) V+; DePuy Synthes, Warsaw, IN, USA). Biomechanical testing was conducted to analyze peak-to-peak displacement, total displacement, and stiffness in following a standardized protocol.
Results
The peak-to-peak displacement under a 200-N load was not significantly different among the groups; however, peak-to-peak displacement under a 600- and 1000-N load as well as total displacement exhibited better stability in PMMA-augmented screw osteosynthesis compared to screw fixation without augmentation. The stiffness of the construct was increased by both CP- and PMMA-based cements.
Conclusion
Addition of an injectable bone cement to screw osteosynthesis is able to increase fixation strength in a biomechanical calcaneal fracture model with synthetic bones. In such cases, PMMA-based cements are more effective than CP-based cements because of their inherently higher compressive strength. However, whether this high strength is required in the clinical setting for early weight-bearing remains controversial, and the non-degradable properties of PMMA might cause difficulties during subsequent interventions in younger patients.