Metallic Biomaterials: Screws that dissolve
Prof. Regine Willumeit-Römer has served as institute director of the Metallic Biomaterials Division at the Institute of Materials Research of the Helmholtz-Zentrum Geesthacht since January 2015. The long-time HZG department head discusses her institute’s research with Erich Wittenberg.
Photo: HZG/ Christian Schmid
What are the tasks and goals of this new division?
As the name indicates, we would like to develop metallic biomaterials, which are essentially implant materials for affi xing and repairing bones. Our main focus lies in measurement and development of magnesium alloys for use in degradable implants. We will also, however, develop titanium alloys for permanent implants that remain in the body.
So, the main priority is to develop magnesium bone implants that no longer need to be removed from the body because they dissolve. This research has been carried out since 2011 in the EU project MagnIM.
That is correct. There are various materials available for this task. Polymers that dissolve, for example, can be used. That’s actually already been done. There are some applications where small polymer screws are utilised for attaching ripped ligaments in knee and shoulder joints. We’re moving in a different direction. We’re using metals that dissolve. Iron, zinc and magnesium are potential candidates. We decided on magnesium because, of the three metals, it basically dissolves fastest and because it can be a very sensible supplement for the body. Magnesium is an extremely important component in the body and, in contrast to polymers, it is also a “load bearing” material – that is, it is more rigid and firm than a polymer material. We also hope to provide greater support for major bone defects with our work.
One cannot simply take a piece of magnesium and produce an implant from it, right? Where‘s the devil the details?
The main problem is actually the degradability of the material. If it dissolves too fast, think of it rather like a fi zzy tablet: it releases a lot of gas and the material disappears quickly. Healing bones require, however, several weeks to months. That is, the material should remain in place within the body for this period of time. Also, the release of hydrogen gas is obviously not something that I would like to see happening in the bones. I therefore need to find a middle ground between a degradation rate that is fast enough, so that the material quickly disappears from the body but is slow enough so that the bones can become suitably accustomed to the implant and can heal themselves while the implant degrades. It is extremely difficult to precisely gauge. There are so many factors that must be considered. Such considerations include selecting the right alloy element, the necessary thermal and surface treatments, which, if done incorrectly, can essentially lead to the material degrading much faster than you‘d like.
"One of the central questions is: how does the material actually degrade in the body and, above all, how can I measure this process?" Photo: iStock/ NikiLitov
Which alloys do you use?
In principle, we work with rare earths as one component. But we’ve also been using silver as an alloy element. Silver is scientifi cally useful for us in adjusting certain material properties and has the added benefit of its antimicrobial effect. The idea was that, by using this implant, it would kill bacteria in the wound during the degradation process. You can, for example, also add calcium as an alloy element. We have a very large box of materials to work with. We begin with alloys, always initially mixing magnesium with an alloy element though actually more complicated mixes, using two or even three additional alloy elements, are conceivable. That is something we’re working on at the moment.
What insights have your studies brought to light?
We worked for a very long time on suitable cell culture experiments. Magnesium’s specific degradation behaviour requires all new experiments. Unfortunately, the standard tests cannot be used at all here, as they would lead to false results. The next problems arise with the surface characterisation and the nature of the implant surface. After we had those under control, we realised that the material was degrading too slowly, though we had discerned that the rates were suitable in cell cultures in a range of about one millimetre per year. Colleagues at the University Clinic Graz carried out animal testing on rats that were, however, substantially slower. This means that we need to retest the corrosion rates in cell cultures to ensure that the rate in the animal matches that of the corrosion rate in the cell culture.
Are your materials produced in Geesthacht?
Yes, partially. The alloys are produced with the help of our colleagues at the Magnesium Innovation Center. The final production, however, takes place elsewhere. It is something that we would like to do ourselves in the future though. We would like to undertake a number of measures for acquiring the most important instruments and machines in order to be able to create the prototypes ourselves. As it turns out, the process ranging from casting the raw material to producing the final screw requires a great many steps, all of which infl uence the material itself. We have therefore said that we must be in the position to optimise and scientifically measure these processes ourselves by manufacturing small batches. An implant manufacturer that produces screws, for example, supplies us in the end with hundreds of screws. If we only need ten in order to tell us that the process unfortunately didn‘t work, then that‘s a complete waste of resources. The manufacturer of course doesn’t make several runs, constantly using new process parameters; they do so using only one set. This is by far insufficient for our scientific work. This means that we would very much like to handle the entire product chain ourselves in the future, here in Geesthacht.
MagnIM was to run for a duration of four years, starting in 2011. Does it end in September of this year?
MagnIM will certainly be ending. We have already started working on acquiring follow-up projects. There are also overlaps with the virtual institute MetBioMat. This is an endeavour supported by the Helmholtz Association, in which twenty-seven partners from northern Germany cooperate in order to put magnesium implant materials more quickly into use. The main focus is the animal studies, which are carried out by this virtual institute. Participants include the University Clinic Hamburg Eppendorf, the Hannover Medical School and the University Clinic Graz. Of course, the work within the new institute division ’Metallic Biomaterials‘ is entirely in line with this research. Even if individual aspects were undertaken through external partners in MagnIM, which cannot continue as they were in the past, we still have a great deal of inhouse capacity to carry out most things ourselves that we began in MagnIM.
Photo: HZG/ Christian Schmid
To what extent have you reached your goals that you set out in MagnIM?
The main objective of MagnIM was the characterisation of implant materials in animals, and that is something we achieved. The materials we wanted to test were even examined once as a small screw and once as a small pin. We therefore now have a very large amount of data available that we need to evaluate. We are meanwhile in the second and, depending on the material, already in the third round of optimisation for even better adaptation of the material for use in organisms.
How long will it take before the implant materials can be used in human clinical trials?
I think it will take quite a long time with the materials that we have just developed. Developing implants for children was one aspect of MagnIM. The use of silver was, for example, controversial even though it possesses antimicrobial properties. It’s a completely different situation with adults. A company will need to decide in the end because we will not carry out clinical studies, and it‘s not at all something we could afford.
What are your next objectives?
I fi rst must see what partners I‘ll continue to cooperate with next year. One of the central questions is: how does the material actually degrade in the body and, above all, how can I measure this process? That is, how can I see what occurs during a period of one year or a year and a half in a living organism?
How do you want to approach this issue?
We will try to develop imaging methods through various externally funded projects. These follow-up projects will include some partners from the virtual institute as well as from MagnIM. Because it is only when we really know what occurs in a living organism can we recreate these experiments in a laboratory and then obtain much more reliable numbers. This is how we can reduce the amount of animal testing in the future. We hope to develop sensors that tell me which proteins are formed from the body during degradation, which cells migrate to the implant site, what kind of chemistry occurs on the implant surface – that is, all these things that concern the biology in a living organism – this is the greatest challenge for me at the moment.
Prof. Annelie Weinberg, Chief Physician at the University of Graz works closely on two projects with Prof. Regine Willumeit- Römer. The trauma surgeon fi nds metallic biomaterials especially promising for paediatric surgical applications. Erich Wittenberg speaks with her about how these materials can be utilised.
"I also believe that we’ll later have access to what we would call ‘design on demand’."- Prof. Annelie Weinberg. Photo: private
Where do the differences lie in handling the material in surgical practice?
The material is more elastic down to its basic properties. At the moment it must therefore remain a bit thicker. If you take, for example, a conventional wire with a diameter of 1.6 millimetres, then you now need one of about 2.24 millimetres here. The dimensions must be greater so that you can keep the same elastic properties, which is important for healing bone fractures.
Where do you see the advantages?
If an implant dissolves and you no longer need to remove it, everyone benefi ts. Children in particular, whose bones heal much faster and are still growing, would benefit greatly. When dealing with adults, we try to generally avoid removing the implant because complications in doing so are relatively high. A bone, however, located where an implant takes over the strain, grows weaker over time. This can lead to problems, especially in the elderly when they already have several implants. Degradable magnesium implants would also be of benefit here.
Can magnesium implants one day completely replace the materials used today?
That depends on many factors. With adults, I see this can be more problematic because, at the end of the day, the question of method comes down to cost. We must also prove that the risk for the patients will be considerably reduced. I also believe that we’ll later have access to what we would call ’design on demand‘. That means that different magnesium alloys will be developed for different applications.
What are your objectives in the projects you’re working on with Prof. Willumeit-Römer?
Our objective is to test the alloys in animals. We receive implants made of magnesium alloys from the HZG and implant them into animals. We then analyse this data. One aim is to also compare the in vitro data with the in vivo data to keep, for example, the amount of animal testing to a minimum.
What results have you attained?
We have managed to place the material in the bones and can demonstrate that this is unproblematic. The material isn’t yet degrading optimally, but we‘re very close. We do at least have candidates that look very promising. It‘s important to adjust the material so that it doesn’t degrade too rapidly. We also worked with a material that had dissolved very quickly and were astounded that the bones could completely heal regardless. This is good news because even if something might not work, it wouldn’t have a negative impact on the bone.
Author: Erich Wittenberg
Published in in2science #2 (July 2015)