5. Results and Discussion
5.5. Comprehensive discussion of used animal models for the investigation of biomaterials for orthopedic applications
In general, animal models are essential for the investigation of biomaterials prior to clinical studies to avoid clinical failure of the material. However, no animal model can precisely predict the material behavior in the target organism, which is predominantly the human being or, in the field of veterinary medicine, companion animals like dogs and cats. Even the special field of application can influence biocompatibility and applicability of a biomaterial. Nevertheless, general properties and local reactions to
different materials can be examined in small and large animal models with following extrapolation to the situation in other animals or humans.
It is necessary to clearly define the particular research question and to use an animal model, which is reproducible and reflects the particular situation being evaluated (DRESPE et al. 2005; PEARCE et al. 2007; CORRALES et al. 2008; MILLS a.
SIMPSON 2012). Additionally, prior to an animal experiment, the three R´s have to be considered: to Reduce, Refine or Replace the animal experiments. In the examination of implant materials, especially magnesium alloys, no in vitro model exists, which can precisely predict implant degradation and biocompatibility. Therefore, material´s examination in animal models is irreplaceable. In the present studies, predominantly the rabbit model was used, although the mouse as small animal model (study XI) and the sheep as large animal model (study XXI) were also implemented in some studies.
While some authors recommended to perform first in vivo studies of degradable biomaterials in small animal models like mice and rats (ZHANG et al. 2009;
CASTELLANI et al. 2011; KRAUS et al. 2012; LINDTNER et al. 2013; WALKER et al.
2014b), other research groups prefer the sheep (WILLBOLD et al. 2013) or the rabbit (WITTE et al. 2007b; LI et al. 2008; WITTE et al. 2010; WONG et al. 2010; ZHANG et al. 2010). In our studies, different factors were considered in the choice of the animal model, like availability, housing, ease of handling, costs, ethics, background data and susceptibility to the disease (AN a. FRIEDMAN 1998). In biomaterial research, especially inflammatory reactions to the material are of special interest as well as degradation, when implanted in subcutaneous tissue. In the present studies, the mouse model was only used for the investigation of osteoconductivity of magnesium.
In contrast to subcutaneous location, an intravascular approach was used, which was established in the research consortium before. Magnesium, titanium and glyconate implants were introduced into intravenous catheters the tail vein was punctured in the
cranial third after manually compression in the anesthetized mice and the implants were pushed into the vein. Degradation rate and tissue reactions could be observed µ-computed tomographically and histologically (MUELLER et al. 2012). Other authors used rats for first investigations of magnesium degradation rates in subcutaneous location (AGHION et al. 2012; WALKER et al. 2014b) or even in orthotopic location (ZHANG et al. 2009; CASTELLANI et al. 2011; KRAUS et al. 2012; LINDTNER et al.
2013). Predominantly a transcortical application of simple pin geometries in the femur was used (CASTELLANI et al. 2011; KRAUS et al. 2012; LINDTNER et al. 2013).
However, rats and mice are very small and more complex implant geometries are difficult. Additionally, for in vivo µ-computed tomography a high resolution is necessary.
The resolution of the used in vivo µ-computer tomograph in the present studies is limited to 41µm, which is borderline for the investigation of small implants especially in an osseous environment, because the density of bone and magnesium implants is very similar. Therefore, in most studies the rabbit was used as alternative. Advantages were the ease in handling and lower costs compared to sheep models, and on the other hand the possibility to use larger implants than in rats and mice. Beside simple pin geometries of various magnesium alloys, which were tested within the intramedullary cavity (studies I, V, VII, VIII, IX, X, XIII, XIV, XV, XXII) simple functional implants like screws and osteosynthesis plates could be examined as well (studies II, XVI, XVIII).
Pull out test of implanted screws with material test systems could be used to evaluate the holding power of magnesium based screws after different implantation times.
Smaller geometries, which would have been necessary for mice and rats, limit these evaluations techniques.
Especially the rabbit tibia model could be established in the last years in our research group and a comparison between different materials was possible due to a standardized approach and implantation in the medullary cavity. The measurement of
force and bending moment data in physiological movement (study VI) secondary offered the possibility for the establishment of simulation models. These models can be used for the adjustment of designs in osteosynthesis systems prior to the evaluation in the animal model. Mechanical parameters can be calculated with these simulations, which may contribute to less material failure in the in vivo situation. More detailed information about animal models in fracture repair is given in study XXI. In magnesium research, many other authors used the rabbit as animal model as well (WITTE et al.
2007b; LI et al. 2008; WITTE et al. 2010; WONG et al. 2010; ZHANG et al. 2010).
However, for more complex implant systems like interlocked intramedullary nailing systems, even the rabbit model is too small. For this purpose the sheep model, which is the predominately used large animal model in fracture repair (studies XXI, XXIV, XXV), was used. Many different fixation techniques like osteosynthesis plates or intramedullary nails were examined in this model as well as bone healing in critical size defects (TEIXEIRA et al. 2007; LU et al. 2009; MUELLER et al. 2009; KLEIN et al.
2010; NIEMEYER et al. 2010; PLECKO et al. 2012; TRALMAN et al. 2012). However, the sheep model has some limitations; for in vivo µ-computed tomography, the sheep was too large and the resolution in clinically used computed tomography was very imprecise for the evaluation of implant degradation in vivo (study XXI). Detailed information about implant volume loss and bone remodeling properties could only be achieved after euthanasia by the use of additional methods like ex vivo µ-CT and histology. Also variances among the individuals were greater than in the used small animals (mice and rabbits). For more reliable statistical results the number of used animals should be increased, but costs and efforts of care often limit this option.
The choice of the animal model and the implant location influence the implant material.
Substantial differences in implant degradation were observed for the same implant
material LAE442 in dependence to the implant location (plate-screw-system degraded much faster than the intramedullary nailing system). It cannot be clearly stated, if these differences only were caused by the variances in the surrounding tissue or additionally by variances in the used animal model. Whereas the plate-screw systems were implanted in the rabbit model, the intramedullary nailing system was tested in the sheep model. Differences in the metabolic rate, which is faster in smaller animals, are a possible explanation for decreased gas formation as well. A comparative study of the degradation of magnesium based implant materials between different animal models does not exist yet.
In conclusion, the use of the animal model has to be carefully chosen prior to the study and should first of all implement the precise research question and second the available possibilities in handling, housing as well as methods for the investigation.
Especially for the development of biomaterials for fracture fixation devices at least for first examination of biocompatibility and calculation of suitable mechanical stabilities the rabbit is a very convenient animal model, whereas for further studies of more complex implant systems the sheep model is more suitable.
Beside these animal models, mice or rats should always be taken into account, especially for first preliminary studies of new biodegradable materials.
6. Summary
In vivo evaluation of degradable magnesium alloys as orthopedic implant material in suitable animal models
Janin Reifenrath
Until today, commonly used implant materials in fracture repair are permanent and need to be removed after the healing process. In the present studies, biodegradable magnesium based implant materials were tested in different animal models for the use as orthopedic implant material in weight bearing applications. Therefore, mechanical strength is required beside a good biocompatibility during the degradation process. As in vitro studies are still not able to represent the complex in vivo situation, examinations in animal models are indispensable prior to clinical studies. In this interdisciplinary collaborative research on the development of magnesium-based implant materials for loaded applications, material and engineering scientists, bio-mechanists, and orthopedic surgeons were implemented. First promising materials were carved out by the use of clinical, radiographical, (µ-) computed tomographical and histological methods as well as biomechanical approaches, predominantly in the rabbit model.
These materials, especially LAE442, were afterwards evaluated in application-oriented studies as osteosynthesis system (plate-screw system and interlocked intramedullary nailing system). While the intramedullary nailing system showed an adequate biocompatibility and very slow implant degradation, the plate screw-system caused massive clinical problems with gas formation and lameness and could not be recommended for the clinical use in the current state. However, the reason for the differences in implant degradation and resultant tissue reactions in the implant surrounding could not be finally resolved. Magnesium degradation is influenced by various factors, including pretreatments which can influence the surface structure,
mechanical stresses during the implantation and differences in the surrounding tissue, especially ion concentrations. Although the intramedullary nailing systems were very promising, additional finite element simulations showed that the mechanical strength is borderline for fracture fixation without an additional stabilization within the first weeks. Further studies should clarify whether positive effects (like reduced stress shielding over time) are superior to the restriction in application.
The evaluation in animal models still remains indispensable, as the degradation in vitro differs from the degradation in vivo. Until now, no system can predict the in vivo situation. Especially the rabbit is a very commonly used and suitable animal model. It combines the ease in housing and handling requirements with the possibility of application oriented testing of implant materials by the use of various imaging techniques, including µ-computed tomography as well as simple biomechanical test.
Only more complex interlocked intramedullary nailing systems were tested in the sheep as large animal model. However, differences in the metabolic rate as well as differences in the bone structure always have to be taken into account, when results are extrapolated to other animals or the human medicine.
Considering the studies together, low inflammatory reactions of the tissues surrounding magnesium based implants are beneficial. If the degradation process is slow, gas which occurs during the degradation process can be resorbed without clinical problems. The use as an osteosynthesis system especially in high loaded applications has to be considered as problematic due to a borderline mechanical stability and high amounts of material. However, smaller implants or lower loaded areas are very promising applications for magnesium based implant materials.
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