Influence of implant base material on secondary bone healing: an in silico study.

The implant material at the fracture site influences fracture healing not only from biological perspective but also from mechanical perspective. Biodegradable implants such as magnesium (Mg) based alloys have shown faster secondary bone healing properties as compared to bioinert implants such as titanium (Ti). The general reasoning behind this is the benefit of Mg from biocompatibility perspectives. We studied the effect of Ti and Mg as base materials for implants from mechanical perspectives, where we focused on the displacements at the fracture site of the tibia and their influence on the stimulus for bone healing. We found out that in comparison to Ti, Mg implants have minimal stress shielding problem, only which led to better mechanical stimulus at the fracture site.

Development of a Bioreactor-Coupled Flow-Cell Setup for 3D In Situ Nanotomography of Mg Alloy Biodegradation.

Functional materials feature hierarchical microstructures that define their unique set of properties. The prediction and tailoring of these require a multiscale knowledge of the mechanistic interaction of microstructure and property. An important material in this respect is biodegradable magnesium alloys used for implant applications. To correlate the relationship between the microstructure and the nonlinear degradation process, high-resolution in situ three-dimensional (3D) imaging experiments must be performed. For this purpose, a novel experimental flow cell is presented which allows for the in situ 3D-nano imaging of the biodegradation process of materials with nominal resolutions below 100 nm using nanofocused hard X-ray radiation from a synchrotron source. The flow cell setup can operate under adjustable physiological and hydrodynamic conditions. As a model material, the biodegradation of thin Mg-4Ag wires in simulated body fluid under physiological conditions and a flow rate of 1 mL/min is studied. The use of two full-field nanotomographic imaging techniques, namely transmission X-ray microscopy and near-field holotomography, is compared, revealing holotomography as the superior imaging technique for this purpose. Additionally, the importance of maintaining physiological conditions is highlighted by the preliminary results. Supporting measurements using electron microscopy to investigate the chemical composition of the samples after degradation are performed.

Strength and ductility loss of Magnesium-Gadolinium due to corrosion in physiological environment: Experiments and modeling.

We propose a computational framework to study the effect of corrosion on the mechanical strength of magnesium (Mg) samples. Our work is motivated by the need to predict the residual strength of biomedical Mg implants after a given period of degradation in a physiological environment. To model corrosion, a mass-diffusion type model is used that accounts for localised corrosion using Weibull statistics. The overall mass loss is prescribed (e.g., based on experimental data). The mechanical behaviour of the Mg samples is modeled by a state-of-the-art Cazacu-Plunkett-Barlat plasticity model with a coupled damage model. This allowed us to study how Mg degradation in immersed samples reduces the mechanical strength over time. We performed a large number of in vitro corrosion experiments and mechanical tests to validate our computational framework. Our framework could predict both the experimentally observed loss of mechanical strength and the ductility due to corrosion for both tension and compression tests.

Exploring the Usability of α-MSH-SM-Liposome as an Imaging Agent to Study Biodegradable Bone Implants In Vivo.

Novel biodegradable metal alloys are increasingly used as implant materials. The implantation can be accompanied by an inflammatory response to a foreign object. For studying inflammation in the implantation area, non-invasive imaging methods are needed. In vivo imaging for the implanted area and its surroundings will provide beneficiary information to understand implant-related inflammation and help to monitor it. Therefore, inflammation-sensitive fluorescent liposomes in rats were tested in the presence of an implant to evaluate their usability in studying inflammation. The sphingomyelin-containing liposomes carrying alpha-melanocyte-stimulating hormone (α-MSH)-peptide were tested in a rat bone implant model. The liposome interaction with implant material (Mg-10Gd) was analyzed with Mg-based implant material (Mg-10Gd) in vitro. The liposome uptake process was studied in the bone-marrow-derived macrophages in vitro. Finally, this liposomal tracer was tested in vivo. It was found that α-MSH coupled sphingomyelin-containing liposomes and the Mg-10Gd implant did not have any disturbing influence on each other. The clearance of liposomes was observed in the presence of an inert and biodegradable implant. The degradable Mg-10Gd was used as an alloy example; however, the presented imaging system offers a new possible use of α-MSH-SM-liposomes as tools for investigating implant responses.

High-resolution ex vivo analysis of the degradation and osseointegration of Mg-xGd implant screws in 3D.

Biodegradable magnesium (Mg) alloys can revolutionize osteosynthesis, because they have mechanical properties similar to those of the bone, and degrade over time, avoiding the need of removal surgery. However, they are not yet routinely applied because their degradation behavior is not fully understood. In this study we have investigated and quantified the degradation and osseointegration behavior of two biodegradable Mg alloys based on gadolinium (Gd) at high resolution. Mg-5Gd and Mg-10Gd screws were inserted in rat tibia for 4, 8 and 12 weeks. Afterward, the degradation rate and degradation homogeneity, as well as bone-to-implant interface, were studied with synchrotron radiation micro computed tomography and histology. Titanium (Ti) and polyether ether ketone (PEEK) were used as controls material to evaluate osseointegration. Our results showed that Mg-5Gd degraded faster and less homogeneously than Mg-10Gd. Both alloys gradually form a stable degradation layer at the interface and were surrounded by new bone tissue. The results were correlated to in vitro data obtained from the same material and shape. The average bone-to-implant contact of the Mg-xGd implants was comparable to that of Ti and higher than for PEEK. The results suggest that both Mg-xGd alloys are suitable as materials for bone implants.

Dynamic in vivo monitoring of fracture healing process in response to magnesium implant with multimodal imaging: pilot longitudinal study in a rat external fixation model.

Rodent models are commonly used in pre-clinical research of magnesium (Mg)-based and other types of biomaterials for fracture treatment. Most studies selected unstable fixation methods, and there is a lack of multimodal longitudinal in vivo monitoring of bone healing. The purpose of this study is to develop a rat femoral fracture model stabilized by external fixation with intra-medullary Mg implant, and to investigate the dynamic bone union process with several imaging techniques offering complementing insights into the process. Pure Mg pins were prepared, followed by an in vitro degradation test. Male Sprague-Dawley rats in the experimental group underwent femoral osteotomy stabilized by external fixators with intra-medullary implantation of Mg pins, and the control group underwent external fixation without intra-medullary implants. Post-operative radiograph, micro-CT and B-mode ultrasonography were acquired directly after surgery, and re-examined at week 4, 8 and 12. Bone tissue volume, in vivo implant degradation, histological staining and MRI images were analyzed using ex vivo samples. Both groups achieved fracture union at week 12, and the dynamic healing process was illustrated by in vivo radiograph, micro-CT and ultrasonography. Bilateral whole femur ex vivo analysis further demonstrated increased ratio of bone tissue volume in the surgical femur with Mg implants, and in vivo degradation of Mg pins was slower than in vitro results. Titanium screws rather than intra-medullary Mg pins were the source of artifact in MRI. This pilot study showed the rat fracture model with external fixation and intra-medullary Mg implantation to be an effective method for dynamic in vivo monitoring of the bone healing process. Future application of the animal model may facilitate pre-clinical translational research of biodegradable orthopaedic implant materials for fracture treatment.

Alloying and Processing Effects on the Microstructure, Mechanical Properties, and Degradation Behavior of Extruded Magnesium Alloys Containing Calcium, Cerium, or Silver.

Magnesium alloys attract attention as degradable implant materials due to their adjustable corrosion properties and biocompatibility. In the last few decades, especially wrought magnesium alloys with enhanced mechanical properties have been developed, with the main aim of increasing ductility and formability. Alloying and processing studies allowed demonstrating the relationship between the processing and the microstructure development for many new magnesium alloys. Based on this experience, magnesium alloy compositions need adjustment to elements improving mechanical properties while being suitable for biomaterial applications. In this work, magnesium alloys from two Mg-Zn series with Ce (ZE) or Ca (ZX) as additional elements and a series of alloys with Ag and Ca (QX) as alloying elements are suggested. The microstructure development was studied after the extrusion of round bars with varied processing parameters and was related to the mechanical properties and the degradation behavior of the alloys. Grain refinement and texture weakening mechanisms could be improved based on the alloy composition for enhancing the mechanical properties. Degradation rates largely depended on the nature of second phase particles rather than on the grain size, but remained suitable for biological applications. Furthermore, all alloy compositions exhibited promising cytocompatibility.

Analysis of the bone ultrastructure around biodegradable Mg-xGd implants using small angle X-ray scattering and X-ray diffraction.

Magnesium alloys are increasingly researched as temporary biodegradable metal implants in bone applications due to their mechanical properties which are more similar to bone than conventional implant metals and the fact that Magnesium occurs naturally within the body. However, the degradation processes in vivo and in particular the interaction of the bone with the degrading material need to be further investigated. In this study we are presenting the first quantitative comparison of the bone ultrastructure formed at the interface of biodegradable Mg-5Gd and Mg-10Gd implants and titanium and PEEK implants after 4, 8 and 12 weeks healing time using two-dimensional small angle X-ray scattering and X-ray diffraction. Differences in mineralization, orientation and thickness of the hydroxyapatite are assessed. We find statistically significant (p < 0.05) differences for the lattice spacing of the (310)-reflex of hydroxyapatite between titanium and Mg-xGd materials, as well as for the (310) crystal size between titanium and Mg-5Gd, indicating a possible deposition of Mg within the bone matrix. The (310) lattice spacing and crystallite size further differ significantly between implant degradation layer and surrounding bone (p < 0.001 for Mg-10Gd), suggesting apatite formation with significant amounts of Gd and Mg within the degradation layer. STATEMENT OF SIGNIFICANCE: Biodegradable Magnesium-based alloys are emerging as a viable alternative for temporary bone implant applications. However, in order to understand if the degradation of the implant material influences the bone ultrastructure, it is necessary to study the bone structure using high-resolution techniques. We have therefore employed 2D small angle X-ray scattering and X-ray diffraction to study the bone ultrastructure surrounding Magnesium-Gadolinium alloys as well as Titanium and PEEK alloys at three different healing times. This is the first time, that the bone ultrastructure around these materials is directly compared and that a statistical evaluation is performed. We found differences indicating a possible deposition of Mg within the bone matrix as well as a local deposition of Mg and/or Gd at the implant site. DATA AVAILABILITY STATEMENT: The raw/processed data required to reproduce these findings cannot be shared at this time as the data also forms part of an ongoing study.

The Effect of Equal-Channel Angular Pressing on the Microstructure, the Mechanical and Corrosion Properties and the Anti-Tumor Activity of Magnesium Alloyed with Silver.

The effect of equal-channel angular pressing (ECAP) on the microstructure, texture, mechanical properties, corrosion resistance and cytotoxicity of two magnesium-silver alloys, Mg-2.0%Ag and Mg-4.0%Ag, was studied. Their average grain size was found to be reduced to 3.2 ± 1.4 µm and 2.8 ± 1.3 µm, respectively. Despite the substantial grain refinement, a drop in the strength characteristics of the alloys was observed, which can be attributed to the formation of inclined basal texture. On a positive side, an increase in tensile ductility to ~34% for Mg-2.0%Ag and ~27% for Mg-4.0%Ag was observed. This effect can be associated with the activity of basal and prismatic slip induced by ECAP. One of the ECAP regimes tested gave rise to a drop in the corrosion resistance of both alloys. An interesting observation was a cytotoxic effect both alloys had on tumor cells in vitro. This effect was accompanied with the release of lactate dehydrogenase, an increase in oxidative stress, coupled with the induction of NO-ions and an increase in the content of such markers of apoptosis as Annexin V and Caspase 3/7. Differences in the chemical composition and the processing history-dependent microstructure of the alloys did not have any significant effect on the magnitude of their antiproliferative effect.

The Effect of Surface Treatments on the Degradation of Biomedical Mg Alloys-A Review Paper.

This report reviews the effects of chemical, physical, and mechanical surface treatments on the degradation behavior of Mg alloys via their influence on the roughness and surface morphology. Many studies have been focused on technically-used AZ alloys and a few investigations regarding the surface treatment of biodegradable and Al-free Mg alloys, especially under physiological conditions. These treatments tailor the surface roughness, homogenize the morphology, and decrease the degradation rate of the alloys. Conversely, there have also been reports which showed that rough surfaces lead to less pitting and good cell adherence. Besides roughness, there are many other parameters which are much more important than roughness when regarding the degradation behavior of an alloy. These studies, which indicate the relationship between surface treatments, roughness and degradation, require further elaboration, particularly for biomedical Mg alloy applications.