Final Report Summary - MAGNIM (Tailored biodegradable magnesium implant materials)
Cost reduction and improvement of the quality of life is a major issue in health care. This challenge can be tackled by intelligent biomaterials and smart implants which are resorbed by the body upon remodelling of the tissue: What is possible for polymer materials should also be realized for biodegradable metallic materials. “MagnIM - Tailored biodegradable magnesium implant materials” trained 12 ESRs from 9 countries (3 male, 9 female) to contribute to this demanding aims by the development of new aluminium free magnesium implant materials with tailored properties specific for a bone related applications especially in children and for sports medicine.
This was achieved by the following three scientific goals in three work packages:
(i) Work package 1: Material development, characterisation and implant production with the objective to modifiy existing Mg implant materials by avoiding Al and still improving mechanical and corrosion properties.
(ii) Work package 2: Degradation behaviour of Mg in vitro with the objective to evaluate the correlation between microstructure and corrosion rates and their interplay with cells from the musculoskeletal system.
and (iii) Work package 3: In vivo studies of biodegradable magnesium based materials aiming at in vivo evaluation of the alloys in a rat/rabbit/sheep model
Overview of results:
In total more than 20 different alloys were produced (mainly binary and ternary composition, also a few quarternary, alloying elements ranged from Ca, Ag, Gd, Nd, Y, Mn, Si to Sr). Depending on their intended use, some contributed to the confirmation of theoretical data such as predictions from phase diagrams, others were tested under different corrosive environments to determine their degradation properties but also to evaluate which corrosion set up would deliver the best matching degradation rates with in vivo data. In parallel the influence of heat treatments or other processing steps such as extrusion were evaluated. By combing all available data, finally two of the new alloys (Mg-2Ag and Mg-10Gd) were selected for first animal trials.
Beside the classical electrochemical and material science approaches to determine mechanical properties, degradation rates and the composition of the degradation layer, also synchrotron based methods such as in situ diffraction were applied. With this method the phases formed during solidification were determined and new phases not expected from existing phase diagrams detected.
The degradation studies did not only deliver averaged corrosion rates but also the compostion of the corrosion layer. An intense search for the influence of different salts and other biological factors (e.g. proteins and cells) revealed that depending on the environment calcium-phosphate precipitates are formed, and cells can change the chemical composition of the corrosion layers located under the cell surface.
When alloys showed sufficient mechanical properties and the average degradation speed was below 1 mm/year the alloys were chosen for cell culture assessment. Here not only cytotoxicity was evaluated. More important were the questions if a stimulative effect in terms of bone formation was observed. Also the influence on macrophages which represents a model for inflammation was studied. Here first indications for an anti-inflammatory function of degradation products were found.
Finally the studies of the materials in two animal models gave first insights about the degradation behaviour and how it scaled with the in vitro experiments. Mg-2Ag and Mg-10Gd pins were introduced into the femora of juvenile rats to monitor the degradation and corresponding bone formation in still growing animals. Very small screws made of Mg-2Ag, Mg-10Gd and WE43 (a well known and slowly degrading material) were inserted into the mandible of adult rats to monitor the degradation at a different implantation site for a different implant geometry. Besides monitoring the degradation by µCT over a period of several months also explants were studied by histology and histomorphometry. In some cases synchrotron tomography (spatial resolution around 2 µm) was merged with histological data. Only then it became obvious that what appeared to be the screw in the X-ray images was already bone visualized by a corresponding staining.
Conclusions: The network covered the full value chain from material development towards in vivo studies. It became obvious that an optimisation especially with regard to material homogeneity and surface properties is the ultimate requirement. In the next step one of the materials will be tested in a large animal model getting closer to an application in humans because the size of the implant is comparable and the mechanical load more pronounced than in a rodant model.
Socio-economic impacts: The network trained in total 12 students who have already or will soon finalize their thesis work. They have become independent and well trained interdisciplinary biomaterials researchers offering a variety of skills necessary to develop implants which will improve the quality of live for all generations.
Contact: Prof. Dr. Regine Willumeit-Römer (regine.willumeit@hzg.de). The address of the project public website is www.magnim.eu.
This was achieved by the following three scientific goals in three work packages:
(i) Work package 1: Material development, characterisation and implant production with the objective to modifiy existing Mg implant materials by avoiding Al and still improving mechanical and corrosion properties.
(ii) Work package 2: Degradation behaviour of Mg in vitro with the objective to evaluate the correlation between microstructure and corrosion rates and their interplay with cells from the musculoskeletal system.
and (iii) Work package 3: In vivo studies of biodegradable magnesium based materials aiming at in vivo evaluation of the alloys in a rat/rabbit/sheep model
Overview of results:
In total more than 20 different alloys were produced (mainly binary and ternary composition, also a few quarternary, alloying elements ranged from Ca, Ag, Gd, Nd, Y, Mn, Si to Sr). Depending on their intended use, some contributed to the confirmation of theoretical data such as predictions from phase diagrams, others were tested under different corrosive environments to determine their degradation properties but also to evaluate which corrosion set up would deliver the best matching degradation rates with in vivo data. In parallel the influence of heat treatments or other processing steps such as extrusion were evaluated. By combing all available data, finally two of the new alloys (Mg-2Ag and Mg-10Gd) were selected for first animal trials.
Beside the classical electrochemical and material science approaches to determine mechanical properties, degradation rates and the composition of the degradation layer, also synchrotron based methods such as in situ diffraction were applied. With this method the phases formed during solidification were determined and new phases not expected from existing phase diagrams detected.
The degradation studies did not only deliver averaged corrosion rates but also the compostion of the corrosion layer. An intense search for the influence of different salts and other biological factors (e.g. proteins and cells) revealed that depending on the environment calcium-phosphate precipitates are formed, and cells can change the chemical composition of the corrosion layers located under the cell surface.
When alloys showed sufficient mechanical properties and the average degradation speed was below 1 mm/year the alloys were chosen for cell culture assessment. Here not only cytotoxicity was evaluated. More important were the questions if a stimulative effect in terms of bone formation was observed. Also the influence on macrophages which represents a model for inflammation was studied. Here first indications for an anti-inflammatory function of degradation products were found.
Finally the studies of the materials in two animal models gave first insights about the degradation behaviour and how it scaled with the in vitro experiments. Mg-2Ag and Mg-10Gd pins were introduced into the femora of juvenile rats to monitor the degradation and corresponding bone formation in still growing animals. Very small screws made of Mg-2Ag, Mg-10Gd and WE43 (a well known and slowly degrading material) were inserted into the mandible of adult rats to monitor the degradation at a different implantation site for a different implant geometry. Besides monitoring the degradation by µCT over a period of several months also explants were studied by histology and histomorphometry. In some cases synchrotron tomography (spatial resolution around 2 µm) was merged with histological data. Only then it became obvious that what appeared to be the screw in the X-ray images was already bone visualized by a corresponding staining.
Conclusions: The network covered the full value chain from material development towards in vivo studies. It became obvious that an optimisation especially with regard to material homogeneity and surface properties is the ultimate requirement. In the next step one of the materials will be tested in a large animal model getting closer to an application in humans because the size of the implant is comparable and the mechanical load more pronounced than in a rodant model.
Socio-economic impacts: The network trained in total 12 students who have already or will soon finalize their thesis work. They have become independent and well trained interdisciplinary biomaterials researchers offering a variety of skills necessary to develop implants which will improve the quality of live for all generations.
Contact: Prof. Dr. Regine Willumeit-Römer (regine.willumeit@hzg.de). The address of the project public website is www.magnim.eu.