Full length articleGadolinium accumulation in organs of Sprague–Dawley® rats after implantation of a biodegradable magnesium-gadolinium alloy
Graphical abstract
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:
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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.
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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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These authors contributed equally to the work.