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Degradation of denuded collagen within adhesive resin-infiltrated dentin is a pertinent problem in dentin bonding. A biomimetic remineralization scheme that incorporates non-classic crystallization pathways of fluidic amorphous nanoprecursors and mesoscopic transformation has been successful in remineralizing resin-free, acid-etched dentin, with evidence of intrafibrillar and interfibrillar remineralization. This study tested the hypothesis that biomimetic remineralization provides a means for remineralizing incompletely infiltrated resin-dentin interfaces created by etch-and-rinse adhesives. The remineralization medium consists of a Portland cement/simulated body fluid that includes polyacrylic acid and polyvinylphosphonic acid biomimetic analogs for amorphous calcium phosphate dimension regulation and collagen targeting. Both interfibrillar and intrafibrillar apatites became readily discernible within the hybrid layers after 2–4 months. In addition, intra-resin apatite clusters were deposited within the porosities of the adhesive resin matrices. The biomimetic remineralization scheme provides a proof-of-concept for the adoption of nanotechnology as an alternative strategy to extend the longevity of resin-dentin bonds.

Purpose The purpose of this study is to compare the progression rate of bone union and clinical outcomes of opening wedge high tibial osteotomy (OWHTO) using allogenous bone chip or tri-calcium phosphate (TCP) granule as bone graft materials. The hypothesis was that the bone union progression in OWHTOs using TCP granule grafts would be comparable to that of OWHTOs using allogenous bone chip grafts. Methods Between 2011 and 2013, 54 patients who had undergone OWHTO for genu varum and osteoarthritis were randomized to one of the two groups at five centres. TCP granule was used to fill the defect in 27 patients and lyophilized allogenous bone chip was used in the other 27 patients. The degree of bone union was classified on a five-point scale and evaluated using plain radiographs of the knee at 6 weeks, 3 months, 6 months, and 12 months postoperatively. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, pain Visual Analogue Scale (VAS) score and complications were also evaluated. Results The highest degree of bone union observed at 6 and 12 months postoperatively was grade 4, and the number of cases of union progression at each time-point was not significantly different between the two groups ( p  > 0.05). WOMAC and pain VAS scores also showed no differences between the two groups. No complications were observed during the 12-month period following OWHTO in either group. Conclusion OWHTO using TCP granule bone substitute showed similar bone union rates and clinical outcomes compared to allogenous bone chip grafts. TCP granule can be used as bone substitutes instead of allogenous bone chip grafts in OWHTO. Level of evidence Level 1.

Crohn’s disease is a modern Western disease characterised by transmural inflammation of the gastrointestinal tract. It is of unknown aetiology, but evidence suggests that it results from a combination of genetic predisposition and environmental factors. Bacterial-sized microparticles (0·1–1·0 µm) are potent adjuvants in model antigen-mediated immune responses and are increasingly associated with disease. Microparticles of TiO2 and aluminosilicate accumulate in macrophages of human gut-associated lymphoid tissue where the earliest signs of lesions in Crohn’s disease are observed. Dietary microparticles are of endogenous or exogenous origin. Endogenous microparticles dominate and are calcium phosphate (most probably hydroxyapatite), which precipitates in the lumen of the mid-distal gastrointestinal tract due to secretion of Ca and phosphate in the succus entericus. Exogenous dietary microparticles are contaminants (soil and/or dust) and food additives. TiO2, for example, is a food colourant, and aluminosilicates are anti-caking agents, although some aluminosilicates occur as natural contaminants. Food additives alone account for ingestion of approximately 1012 particles/person per d. Possible mechanisms for the role of exogenous and endogenous dietary microparticles in promoting toleragenic or immune responses of gastrointestinal mucosal phagocytosis are discussed. In a double-blind randomised pilot study we have shown that a diet low in Ca and exogenous microparticles appears to alleviate the symptoms of ileal Crohn’s disease, with a significant (P = 0·002) improvement in the Crohn’s disease activity index. A multi-centre trial and further mechanistic studies at the cellular level are underway.

Implant-Insertion-Torque-Value (ITV) proved to be a significant clinical parameter to predict long term implant success-rates and to decide upon immediate loading. The study evaluated ITVs, when four different and commonly used biomaterials were used in sinuslift-procedures compared to natural subantral bone in two-stage-implant-procedures. The tHUCSL-INTRALIFT-method was chosen for sinuslifting in 155 sinuslift-sites for its minimal invasive transcrestal approach and scalable augmentation volume. Four different biomaterials were inserted randomly (easy-graft CRYSTAL n = 38, easy-graft CLASSIC n = 41, NanoBone n = 42, BioOss n = 34), 2 ccm in each case. After a mean healing period of 8,92 months uniform tapered screw Q2-implants were inserted and Drill-Torque-Values (DTV) and ITV were recorded and compared to a group of 36 subantral sites without need of sinuslifting. DTV/ITV were processed for statistics by ANOVA-tests. Mean DTV/ITV obtained in Ncm were: Control Group 10,2/22,2, Bio-Oss 12,7/26,2, NanoBone 17,5/33,3, easy-graft CLASSIC 20,3/45,9, easy-graft CRYSTAL 23,8/56,6 Ncm, significance-level of differences throughout p < 0,05. Within the limits of this study the results suggest self-hardening solid-block-like bone-graft-materials to achieve significantly better DTV/ITV than loose granulate biomaterials for its suspected improvement of vascularization and mineralization of the subantral scaffold by full immobilization of the augmentation site towards pressure changes in the human sinus at normal breathing.

Mineralisation of calcium phosphates in bone has been proposed to proceed via an initial amorphous precursor phase which transforms into nanocrystalline, carbonated hydroxyapatite. While calcium phosphates have been under intense investigation, the exact steps during the crystallisation of spherical amorphous particles to platelet-like bone apatite are unclear. Herein, we demonstrate a detailed transformation mechanism of amorphous calcium phosphate spherical particles to apatite platelet-like crystals, within the confined nanodomains of a bone-inspired nanocomposite. The transformation is initiated under the presence of humidity, where nanocrystalline areas are formed and crystallisation advances via migration of nanometre sized clusters by forming steps at the growth front. We propose that such transformation is a possible crystallisation mechanism and is characteristic of calcium phosphates from a thermodynamic perspective and might be unrelated to the environment. Our observations provide insight into a crucial but unclear stage in bone mineralisation, the origins of the nanostructured, platelet-like bone apatite crystals. The growth of apatite crystals from amorphous calcium phosphate is an area of intense study. Here, the authors report on the use of high resolution TEM imaging to provide evidence of nucleation clusters in the transformation process

Some compositional and structural features of mature bone mineral particles remain unclear. They have been described as calcium-deficient and hydroxyl-deficient carbonated hydroxyapatite particles in which a fraction of the PO 4 3− lattice sites are occupied by HPO 4 2− ions. The time has come to revise this description since it has now been proven that the surface of mature bone mineral particles is not in the form of hydroxyapatite but rather in the form of hydrated amorphous calcium phosphate. Using a combination of dedicated solid-state nuclear magnetic resonance techniques, the hydrogen-bearing species present in bone mineral and especially the HPO 4 2− ions were closely scrutinized. We show that these HPO 4 2− ions are concentrated at the surface of bone mineral particles in the so-called amorphous surface layer whose thickness was estimated here to be about 0.8 nm for a 4-nm thick particle. We also show that their molar proportion is much higher than previously estimated since they stand for about half of the overall amount of inorganic phosphate ions that compose bone mineral. As such, the mineral-mineral and mineral-biomolecule interfaces in bone tissue must be driven by metastable hydrated amorphous environments rich in HPO 4 2− ions rather than by stable crystalline environments of hydroxyapatite structure.

Synthetic hydrogels are here created by enzyme-induced mineralization of hydrogel networks, yielding materials that are tough yet impressively stiff, with calcium phosphate particles distributed homogeneously throughout the network. Synthetic hydrogels get tough and stiff Natural materials such as cartilage and skin have a combination of toughness (meaning they are hard to fracture) and stiffness (meaning they are resistant to bending) that is difficult to emulate in synthetic hydrogels. Previously reported tough hydrogels owed their toughness to their ability to deform by stretching, but they lacked stiffness. Here Joerg Tiller and colleagues create hydrogels that are both tough and stiff by generating in situ amorphous calcium phosphate nanoparticles that are homogenously distributed throughout the hydrogel matrix. The resulting structures are tougher than most water-swollen synthetic hydrogels, and are stiffer than their natural counterparts. The highly filled composite materials can even be designed to be optically transparent, and they remain stretchable even when notched with a razor blade. The researchers attribute the stiffness of these materials to the formation of a percolated network of the calcium phosphate nanoparticles throughout the hydrogel. The cartilage and skin of animals, which are made up of more than fifty per cent water, are rather stiff (having elastic moduli of up to 100 megapascals) 1 , 2 as well as tough and hard to break (with fracture energies of up to 9,000 joules per square metre) 3 , 4 . Such features make these biological materials mechanically superior to existing synthetic hydrogels. Lately, progress has been made in synthesizing tough hydrogels, with double-network hydrogels achieving the toughness of skin 5 and inorganic–organic composites showing even better performance 6 . However, these materials owe their toughness to high stretchability; in terms of stiffness, synthetic hydrogels cannot compete with their natural counterparts, with the best examples having elastic moduli of just 10 megapascals or less 7 , 8 , 9 , 10 , 11 . Previously, we described the enzyme-induced precipitation and crystallization of hydrogels containing calcium carbonate, but the resulting materials were brittle 12 . Here we report the enzyme-induced formation of amorphous calcium phosphate nanostructures that are homogenously distributed within polymer hydrogels. Our best materials have fracture energies of 1,300 joules per square metre even in their fully water-swollen state—a value superior to that of most known water-swollen synthetic materials. We are also able to modulate their stiffness up to 440 megapascals, well beyond that of cartilage and skin. Furthermore, the highly filled composite materials can be designed to be optically transparent and to retain most of their stretchability even when notched. We show that percolation drives the mechanical properties, particularly the high stiffness, of our uniformly mineralized hydrogels.

The surface-directed mineralization of calcium phosphate from simulated body fluid is studied by cryogenic transmission electron microscopy. Prenucleation clusters aggregate close to the surface, then amorphous calcium phosphate forms in this region, leading to the nucleation of oriented apatite crystals at the surface. Unravelling the processes of calcium phosphate formation 1 , 2 , 3 , 4 is important in our understanding of both bone and tooth formation 5 , 6 , 7 , and also of pathological mineralization, for example in cardiovascular disease 8 , 9 , 10 . Serum is a metastable solution from which calcium phosphate precipitates in the presence of calcifiable templates such as collagen, elastin and cell debris 11 , 12 . A pathological deficiency of inhibitors leads to the uncontrolled deposition of calcium phosphate. In bone and teeth the formation of apatite crystals is preceded by an amorphous calcium phosphate (ACP) precursor phase 13 , 14 . ACP formation is thought to proceed through prenucleation clusters—stable clusters that are present in solution already before nucleation—as was recently demonstrated for CaCO 3 (refs  15 16 ). However, the role of such nanometre-sized clusters as building blocks 2 for ACP has been debated for many years. Here we demonstrate that the surface-induced formation of apatite from simulated body fluid 17 , 18 starts with the aggregation of prenucleation clusters leading to the nucleation of ACP before the development of oriented apatite crystals.

The Western pattern diet is rich not only in fat and calories but also in phosphate. The negative effects of excessive fat and calorie intake on health are widely known, but the potential harms of excessive phosphate intake are poorly recognized. Here, we show the mechanism by which dietary phosphate damages the kidney. When phosphate intake was excessive relative to the number of functioning nephrons, circulating levels of FGF23, a hormone that increases the excretion of phosphate per nephron, were increased to maintain phosphate homeostasis. FGF23 suppressed phosphate reabsorption in renal tubules and thus raised the phosphate concentration in the tubule fluid. Once it exceeded a threshold, microscopic particles containing calcium phosphate crystals appeared in the tubule lumen, which damaged tubule cells through binding to the TLR4 expressed on them. Persistent tubule damage induced interstitial fibrosis, reduced the number of nephrons, and further boosted FGF23 to trigger a deterioration spiral leading to progressive nephron loss. In humans, the progression of chronic kidney disease (CKD) ensued when serum FGF23 levels exceeded 53 pg/mL. The present study identified calcium phosphate particles in the renal tubular fluid as an effective therapeutic target to decelerate nephron loss during the course of aging and CKD progression.

Engineered nanoparticles that respond to pathophysiological parameters, such as pH or redox potential, have been developed as contrast agents for the magnetic resonance imaging (MRI) of tumours. However, beyond anatomic assessment, contrast agents that can sense these pathological parameters and rapidly amplify their magnetic resonance signals are desirable because they could potentially be used to monitor the biological processes of tumours and improve cancer diagnosis. Here, we report an MRI contrast agent that rapidly amplifies magnetic resonance signals in response to pH. We confined Mn 2+ within pH-sensitive calcium phosphate (CaP) nanoparticles comprising a poly(ethylene glycol) shell. At a low pH, such as in solid tumours, the CaP disintegrates and releases Mn 2+ ions. Binding to proteins increases the relaxivity of Mn 2+ and enhances the contrast. We show that these nanoparticles could rapidly and selectively brighten solid tumours, identify hypoxic regions within the tumour mass and detect invisible millimetre-sized metastatic tumours in the liver. A magnetic resonance imaging contrast agent that amplifies its signal in response to pH is used to rapidly identify tumours, report hypoxic regions in the tumour and detect millimetre-sized metastatic tumours in the liver of animals.