Iron in Hydroxyapatite: Interstitial or Substitution Sites?

Iron-doped hydroxyapatite (Fe-HAp) is regarded as a promising magnetic material with innate biocompatibility. Despite the many studies reported in the literature, a detailed theoretical description of Fe inclusions is still missing. There is even no consensual view on what kind of Fe defects take place in Fe-HAp-iron interstitial or calcium substitutions? In order to address these questions, we employ modern first-principles methodologies, including hybrid density functional theory, to find the geometry, electronic, magnetic and thermodynamic properties of iron impurities in Fe-HAp. We consider a total of 26 defect configurations, including substitutional (phosphorus and calcium sites) and interstitial defects. Formation energies are estimated considering the boundaries of chemical potentials in stable hydroxyapatite. We show that the most probable defect configurations are: Fe3+ and Fe2+ substitutions of Ca(I) and Ca(II) sites under Ca-poor conditions. Conversely, Fe interstitials near the edge of the hydroxyl channel are favored in Ca-rich material. Substitutional Fe on the P site is also a probable defect, and unlike the other forms of Fe, it adopts a low-spin state. The analysis of Fe K-XANES spectra available in the literature shows that Fe-HAp usually contains iron in different configurations.

Cu-doping of calcium phosphate bioceramics: From mechanism to the control of cytotoxicity.

In this study, the Cu-doping mechanism of Biphasic Calcium Phosphate (BCP) was thoroughly investigated, as was its ionic release behavior, in order to elucidate cytotoxicity features of these bioceramics. BCP are composed of hydroxyapatite (Ca10(PO4)6(OH)2) and ß-TCP (Ca3(PO4)2). The two phases present two different doping mechanisms. Incorporation into the ß-TCP structure is achieved at around 700 °C thanks to a substitution mechanism leading to the Cu-doped Ca3-xCux(PO4)2 compound. Incorporation into the HAp structure is achieved thanks to an interstitial mechanism that is limited to a Cu-poor HAp phase for temperatures below 1100 °C (Ca10Cux(PO4)6(OH)2-2xO2x with x < 0.1). Above 1100 °C, the same interstitial mechanism leads to the formation of a Cu-rich HAp mixed-valence phase (Ca10Cu2+xCu+y(PO4)6(OH)2-2x-yO2x+y with x + y ∼ 0.5). The formation of both high-temperature Cu-doped α-TCP and Cu3(PO4)2 phases above 1100 °C induces a transformation into the Cu-rich HAp phase on cooling. The linear OCuO oxocuprate entity was confirmed by EXAFS spectroscopy, and the mixed Cu+/Cu2+ valence was evidenced by XPS analyses. Ionic releases (Cu+/Cu2+, Ca2+, PO42- and OH-) in water and in simulated body media were investigated on as-synthesized ceramics to establish a pretreatment before biological applications. Finally the cytotoxicity of pretreated disks was evaluated, and results confirm that Cu-doped BCP samples are promising bioceramics for bone substitutes and/or prosthesis coatings. STATEMENT OF SIGNIFICANCE: Biphasic Calcium Phosphates (BCP) are bioceramics composed of hydroxyapatite (HAp, Ca10(PO4)6(OH)2) and beta-Tricalium Phosphate (ß-TCP, Ca3(PO4)2). Because their chemical and mineral composition closely resembles that of the mineral component of bone, they are potentially interesting candidates for bone repair surgery. Doping can advantageously be used to improve their biological behaviors; however, it is important to describe the doping mechanism of BCP thoroughly in order to fully appraise the benefit of the doping process. The present paper scrutinizes in detail the incorporation of copper cation in order to correctly interpret the behavior of the Cu-doped bioceramic in biological fluid. The understanding of the copper doping mechanism, related to doping mechanism of others 3d-metal cations, makes it possible to explain the rates and kinetic of release of the dopant in biological medium. Finally, the knowledge of the behavior of the copper doped ceramic in biological environment allowed the tuning of its cytotoxicity properties. The present study resulted on pre-treated ceramic disks which have been evaluated as promising biocompatible ceramic for bone substitute and/or prosthesis coating: good adherence of bone marrow cells with good cell viability.

First-Row Transition Metal Doping in Calcium Phosphate Bioceramics: A Detailed Crystallographic Study.

Doped calcium phosphate bioceramics are promising materials for bone repair surgery because of their chemical resemblance to the mineral constituent of bone. Among these materials, BCP samples composed of hydroxyapatite (Ca10(PO4)6(OH)2) and ß-TCP (Ca3(PO4)2) present a mineral analogy with the nano-multi-substituted hydroxyapatite bio-mineral part of bones. At the same time, doping can be used to tune the biological properties of these ceramics. This paper presents a general overview of the doping mechanisms of BCP samples using cations from the first-row transition metals (from manganese to zinc), with respect to the applied sintering temperature. The results enable the preparation of doped synthetic BCP that can be used to tailor biological properties, in particular by tuning the release amounts upon interaction with biological fluids. Intermediate sintering temperatures stabilize the doping elements in the more soluble ß-TCP phase, which favors quick and easy release upon integration in the biological environment, whereas higher sintering temperatures locate the doping elements in the weakly soluble HAp phase, enabling a slow and continuous supply of the bio-inspired properties. An interstitial doping mechanism in the HAp hexagonal channel is observed for the six investigated cations (Mn2+, Fe3+, Co2+, Ni2+, Cu2+ and Zn2+) with specific characteristics involving a shift away from the center of the hexagonal channel (Fe3+, Co2+), cationic oxidation (Mn3+, Co3+), and also cationic reduction (Cu⁺). The complete crystallochemical study highlights a complex HAp doping mechanism, mainly realized by an interstitial process combined with calcium substitution for the larger cations of the series leading to potentially calcium deficient HAp.

Atomic scale modeling of iron-doped biphasic calcium phosphate bioceramics.

Biphasic calcium phosphates (BCPs) are bioceramics composed of hydroxyapatite (HAp, Ca10(PO4)6(OH)2) and beta-Tricalcium Phosphate (ß-TCP, Ca3(PO4)2). Because their chemical and mineral composition closely resembles that of the mineral component of bone, they are potentially interesting candidates for bone repair surgery, and doping can advantageously be used to improve their biological behavior. However, it is important to describe the doping mechanism of BCP thoroughly in order to be able to master its synthesis and then to fully appraise the benefit of the doping process. In the present paper we describe the ferric doping mechanism: the crystallographic description of our samples, sintered at between 500°C and 1100°C, was provided by Rietveld analyses on X-ray powder diffraction, and the results were confirmed using X-ray absorption spectroscopy and 57Fe Mössbauer spectrometry. The mechanism is temperature-dependent, like the previously reported zinc doping mechanism. Doping was performed on the HAp phase, at high temperature only, by an insertion mechanism. The Fe3+ interstitial site is located in the HAp hexagonal channel, shifted from its centre to form a triangular three-fold coordination. At lower temperatures, the Fe3+ are located at the centre of the channel, forming linear two-fold coordinated O-Fe-O entities. The knowledge of the doping mechanism is a prerequisite for a correct synthesis of the targeted bioceramic with the adapted (Ca+Fe)/P ratio, and so to be able to correctly predict its potential iron release or magnetic properties. STATEMENT OF SIGNIFICANCE: Biphasic calcium phosphates (BCPs) are bioceramics composed of hydroxyapatite (HAp, Ca10(PO4)6(OH)2) and beta-Tricalium Phosphate (ß-TCP, Ca3(PO4)2). Because their chemical and mineral composition closely resembles that of the mineral component of bone, they are potentially interesting candidates for bone repair surgery. Doping can advantageously be used to improve their biological behaviors and/or magnetic properties; however, it is important to describe the doping mechanism of BCP thoroughly in order to fully appraise the benefit of the doping process. The present paper scrutinizes in detail the incorporation of ferric cation in order to correctly interpret the behavior of the iron-doped bioceramic in biological fluid. The temperature dependent mechanism has been fully described for the first time. And it clearly appears that temperature can be used to design the doping according to desired medical application: blood compatibility, remineralization, bactericidal or magnetic response.

X-ray absorption spectroscopy shining (synchrotron) light onto the insertion of Zn2+ in calcium phosphate ceramics and its influence on their behaviour under biological conditions.

The present study gives a fine description of the Zn2+ location in Zn-doped Biphasic Calcium Phosphate (BCP) samples heat treated between 500 °C and 1100 °C. Structural considerations were used to explain the sample interactions with biological fluid (DMEM). X-ray Absorption Spectroscopy (XAS) experiments were used to characterize the powdered samples. The main results (1) indicate the presence of Zn2+ complexes physisorbed at the HAp surface for a sintering temperature of 500 °C, (2) confirm the insertion of Zn2+ into the ß-TCP phase using a substitution mechanism for a sintering temperature around 700 °C, and (3) fully describe the insertion of Zn2+ into the HAp phase by an interstitial mechanism for heat treatment above 900 °C (composition Ca10Znx(PO4)6(OH)2-2xO2x; xmax∼ 0.25). The formation of the linear O-Zn-O entity with dZn-O = 1.72(2) Å has been clearly evidenced by Fourier transform amplitude fitting in the R-space (Zn two-fold coordination unambiguously described for the first time). The mineralisation stimulatory effect of Zn2+ incorporated into BCP has been explained by two different mechanisms. For samples heat treated between 500 °C and 800 °C, the stimulatory effect is attributed to the presence of soluble Zn2+ species: Zn2+ physisorbed at the HAp surface for sintering treatment around 500 °C and Zn2+ incorporated into about 20 wt% (weight percent) of the soluble Zn-doped ß-TCP phase for sintering treatment around 800 °C. A sintering temperature above 900 °C led to the formation of an extremely weakly soluble and well-crystallized Zn-doped HAp phase which acts by facilitating the nucleation of a calcium phosphate phase at its surface.

On the effect of temperature on the insertion of zinc into hydroxyapatite.

Rietveld analysis of X-ray powder diffraction patterns recorded from 28 hydroxyapatite (HAp) samples containing various amounts of zinc (0, 1.6, 3.2 and 6.1wt.% Zn) and heat treated at various temperatures (between 500°C and 1100°C) has enabled the Zn insertion mechanism into the HAp crystal structure to be finely characterized. The formation of Zn-doped HAp was achieved above 900°C only. Zn-doped HAp has the Ca(10)Zn(x)(PO(4))(6)(OH)(2-2)(x)O(2)(x) (0