Elsevier

Acta Biomaterialia

Volume 48, 15 January 2017, Pages 521-529
Acta Biomaterialia

Full length article
Gadolinium accumulation in organs of Sprague–Dawley® rats after implantation of a biodegradable magnesium-gadolinium alloy

https://doi.org/10.1016/j.actbio.2016.11.024Get rights and content

Abstract

Biodegradable magnesium implants are under investigation because of their promising properties as medical devices. For enhancing the mechanical properties and the degradation resistance, rare earth elements are often used as alloying elements.

In this study Mg10Gd pins were implanted into Sprague–Dawley® rats. The pin volume loss and a possible accumulation of magnesium and gadolinium in the rats’ organs and blood were investigated in a long-term study over 36 weeks. The results showed that Mg10Gd is a fast disintegrating material. Already 12 weeks after implantation the alloy is fragmented to smaller particles, which can be found within the intramedullary cavity and the cortical bones. They disturbed the bone remodeling until the end of the study.

The results concerning the elements’ distribution in the animals’ bodies were even more striking, since an accumulation of gadolinium could be observed in the investigated organs over the whole time span. The most affected tissue was the spleen, with up to 3240 μg Gd/kg wet mass, followed by the lung, liver and kidney (up to 1040, 685 and 207 μg Gd/kg). In the brain, muscle and heart, the gadolinium concentrations were much smaller (less than 20 μg/kg), but an accumulation could still be detected. Interestingly, blood serum samples showed no accumulation of magnesium and gadolinium.

This is the first time that an accumulation of gadolinium in animal organs was observed after the application of a gadolinium-containing degradable magnesium implant. These findings demonstrate the importance of future investigations concerning the distribution of the constituents of new biodegradable materials in the body, to ensure the patients’ safety.

Statement of Significance

In the last years, biodegradable Mg alloys are under investigation due to their promising properties as orthopaedic devices used for bone fracture stabilization. Gadolinium as Rare Earth Element enhances the mechanical properties of Mg-Gd alloys but its toxicity in humans is still questionable. Up to now, there is no study investigating the elements’ metabolism of a REE-containing Magnesium alloy in an animal model. In this study, we examined the gadolinium distribution and accumulation in rat organs during the degradation of Mg10Gd. Our findings showed that Gd is accumulating in the animal organs, especially in spleen, liver and kidney. This study is of crucial benefit regarding a safe application of REE-containing Magnesium alloys in humans.

Introduction

In the last years different bioresorbable implants have been under investigation due to their promising properties as biomedical devices for vascular stents and orthopaedic implants. Biodegradable magnesium (Mg) implants can be used to fix bone fractures and consequently no second surgery for explantation is necessary [1], [2]. Mg implants show high biocompatibility because they are non-toxic to the human body and exhibit low stress shielding [1], [3]. As a drawback, Mg shows very high degradation rates when it is in contact with aqueous body fluids [4]. This problem can be eliminated either by alloying Mg with different elements such as rare earth elements (REE) or modifying the implants’ surface [1], [5].

There are several chemical elements which are used in Mg alloys. For example, aluminum, zinc, manganese, calcium, zirconium or REE are used in order to enhance the mechanical and physical properties and increase the degradation resistance [6], [7], [8], [9]. In our study we used the gadolinium (Gd) as alloying element. It is reported that up to 10% of Gd in the material improve the corrosion performance of the material [8] and additional in vitro immersion tests have demonstrated a slow degradation velocity of Mg10Gd alloy which was promising [10], [11], [12].

In general, Gd is considered to be toxic when it is present as free ion, but has very low toxicity to mammals when it is chelated [13], because this restricts the ion release [14]. The chelator inhibits interactions of Gd ions with the tissues and enables rapid renal excretion of Gd. As a result, Gd biotransformation or accumulation in the body is minimised [15].

Such Gd complexes are used in clinical applications as contrast agents in magnetic resonance imaging (MRI) [16]. However, it has been recently discovered that these Gd complexes may cause a very severe complication termed nephrogenic systemic fibrosis (NSF) in patients with chronic kidney failure, which can even be fatal [17]. Furthermore, it has become apparent that Gd can accumulate in the body of animals and humans after administration of Gd containing MRI contrast agents [18], for example in the bone [19], in the liver [20], or even in the brain [21]. Lately, there was also a report of high Gd concentrations in the skin of a patient, eleven and eight years after two applications of Gd based contrast agents. It was speculated that the main chemical form of the Gd deposits in the skin was Gd phosphate, but small amounts of intact contrast agent (Gd-HP-DO3A) were found as well [22]. Still, the consequences of Gd deposition in the human body are yet unknown [23]

Of course, the administration of solutions containing Gd as a salt or as a chelated complex cannot be compared to the implantation of Gd alloys into bone tissue, but there is a lack of reliable systemic toxicity data about these biodegradable materials. For example, the element’s distribution and its clearance from the body have never been reported before.

Generally, it is known that REE can have toxic effects and can cause negative health effects in mammals [13]. The outcomes of a number of animal studies on the toxicity of REEs (Cerium (Ce), dysprosium, Gd, lanthanum (La), neodymium and yttrium) are summarized by Pagano et al. [24]. The major part of the other existing literature only focuses on Ce and La, whereas the other REEs are rarely considered.

There are some in vitro studies on the cytotoxicity of some Mg-REE alloys [25], [26], but their significance for human applications is questionable. Even though in vivo experiments on the materials’ toxicities exist [2], [27], [28], [29], they only address the effects on the biological tissues that are in close proximity to the implant, but never evaluate any possible systemic effects [30]. However, such studies would be crucially important for novel materials.

For this reason, we investigated the Gd and Mg levels in different organs and blood serum samples of Sprague–Dawley® rats after implantation of a Mg10Gd pin, along with the degradation behaviour of the implant at different time points in a long term study of 36 weeks.

Section snippets

Implant

For this study, a Mg10Gd alloy was used. It was produced by the Helmholz Zentrum (HZG), Geesthacht, Germany. For the casting, pure Mg (99.99%) and Gd (99.95%) were used and produced by permanent mould direct chill casting. The casting and extrusion processes are described in more detail elsewhere [11]. After production, the samples were sterilized by gamma radiation dose at 29.2 kGy (BBF GmbH, Stuttgart, Germany).

In vivo experiments

The animal experiments were performed under ethical approval and were authorized by

Pin volume loss μCT

The pin volume loss of the Mg10Gd pins, which illustrates the pin degradation, and high resolution images of the μCT scan are shown in Fig. 1.

The pin volume loss of the Mg10Gd alloy is significantly increased 4 weeks after the operation. Pin volume loss could not be evaluated at 12, 24 and 36 weeks after the implantation because the pins disintegrated in small particles. The high increase of the pin volume loss 4 weeks after the operation revealed a fast disintegrating Mg10Gd material.

Discussion

The present study was focused on the distribution and accumulation of Gd during the degradation of Mg10Gd alloy in a growing male Sprague–Dawley® rat model. Regarding the cytotoxicity of this alloy, studies in in vitro cell experiments have already shown a good cytocompatibility in primary pre-osteoblast cells [11], in human umbilical cord perivascular cells (HUCPV) [12] and in human reaming debris-derived cells (HRD) [32]. In vitro cell experiments of GdCl3 have also shown good viability of

Conclusions

This is the first study that has investigated the distribution and accumulation of Gd in different organs of male Sprague–Dawley® rats after implantation of a Gd containing bioresorbable Mg material (Mg10Gd) used for osteosyntesis. Our results showed the following:

  • Mg10Gd is a fast, and not homogeneously, disintegrating material and remnants of the Mg10Gd are still visible even 36 weeks after the implantation, although the degradation in vitro tests showed that a homogeneous degrading alloy.

  • Mg is

Acknowledgements

This work was supported by European FP7 Marie Curie Program (Project Number: 289163), by Helmholtz Virtual Institute VH-VI-523 (In vivo studies of biodegradable magnesium based implant materials) and by NAWI Graz. The authors would like to thank Prof Regine Willumeit-Römer and Gábor Szakács for their work in the material production and their valuable help, Johannes Eichler for the valuable help during the surgery and Claudia Kleinhans for the support. Furthermore, the authors appreciate the

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