Worked to the Bone

In the mobiLAB-4D project, the members of our expert panel are performing joint research into how the surfaces of implants can be improved to avoid clinical complications. For this purpose, they employ state-ofthe- art in vitro methods, microproduction technologies, and imaging techniques. In an expert interview, the three discuss how this complex collaboration takes place and whether organ-on-a-chip technologies could replace animal testing in the future.


Complications following the insertion of dental, hip, or knee implants are extremely stressful for affected patients and can lead to additional surgeries. The mobiLAB-4D project aims to reduce such complications:

  • Release of nanoparticles: The metallic implant should release as little material as possible into the surrounding tissue.
  • Toxic effects: The particles released must not be toxic.
  • Problems with osseointegration: The implant should integrate itself into the existing bone as well as possible.
  •  Peri-implantitis: Inflammation of the surrounding tissue due to the ingress of germs needs to be prevented.

These problems are to be avoided through optimization of the surface structure and material of the implants. The project partners are therefore looking into implant surfaces and materials that are particularly suited for use in the human body.

futur: Dr. Schoon, how has research on orthopedic materials evolved as a result of recent breakthroughs in microfluidics?


We are currently witnessing major changes in the preclinical testing of implant materials. Our goal is to be able to make better predictions in the future, with respect to reactions such as bone ingrowth of implant materials, in human in vitro models compared to animal models. This way, we hope to further improve patient safety.

futur: Mr. Schweitzer, from the perspective of a production engineer: What makes working with patient samples and the microfluidic chips you obtained from them so challenging?


The challenge is to ensure reliable transport. We need to be able to culture the cells on site for the 4D measurement in a synchrotron facility in a non-trivial environment just as well as in the lab. In order to do this, we need to keep all parameters that are important for cell growth stable at all times, such as the temperatures and CO2 saturation. We also need to be able to constantly guarantee the sterility of the chip systems, even during transport.

futur: This means that a lot of effort goes into making the samples suitable for measuring them in the synchrotron. Dr. Hesse, what are the advantages of 4D microtomography in a synchrotron as compared to other imaging methods?


In the synchrotron, up to one hundred billion times more radiation is generated than in the laboratory. This extremely high X-ray intensity allows for better imaging. Synchrotron radiation is also coherent radiation. This equates to higher contrast for various material phases. Bone is a dynamic material, and we need to be able to identify extremely minute differences in its mineralization in 3D. Almost nothing else can compete with the synchrotron CT to comply with these requirements. With constantly improving hardware, he imaging can also be performed in such short and stable sequences that we can examine samples in a time-resolved manner, i.e., at several different points in time. The difficulty faced by our approach are the particularly long time sequences. The remodeling kinetics of bone are in the range of days, weeks, and sometimes even months. We need a system that will remain stable over such a long period of time.


The method developed can also be used with other long-term applications, for example the bio-degradation of materials or even corrosion processes.

Die European Synchrotron Radiation Facility (ESRF) in Grenoble

futur: Do the samples remain in the synchrotron for the duration, or do you remove them and then return them later?


The X-radiation procedure only requires a few minutes in each case. Subsequently, samples are further cultivated on site for a few days in the laboratories. This is why the mobile measurement and transport unit being developed at Fraunhofer IPK is so important. It allows us to transport the chip systems that are currently at the Charité or in Greifswald, such that we can continue to culture them for weeks at the synchrotron in Grenoble or Paris, where we perform most of our work.


After each measurement, samples need to be returned to the organ-on-a-chip via a double door system for further culturing. If a problem occurs during this process, e.g. due to contamination (e.g. bacterial), we have to stop the tests. That is why we need to ensure that everything remains sterile at all times, both the measurement chamber as well as the chips.

futur: The consortium for your joint research project is an interdisciplinary one, with specialists from fields as diverse as medical research, radiation physics and production engineering. How does this influence your work?


By working with experts from other fields, you stand to learn something yourself. I was at the synchrotron facility in Grenoble for the first time in 2018 with Dr. Hesse. We would not have been able to gain direct access without an expert, our physicist. However, this technology is quintessential for answering our questions in any relevant fashion. That is why this relationship is so very important.


The collaboration on mobi- LAB-4D was initiated by Luiz Schweitzer, who recognized relatively early on what we can achieve together. For our research, it is key to make existing lab-on-a-chip systems synchrotron-compatible. Equally important is an understanding of and the evaluation of synchrotron CTs and the handling of cell samples. This interdisciplinarity is crucial.


Thanks to this project, we have also come up with many ideas on how to continue collaborating on other clinical aspects, such as degradable implant materials. With clinical input from the University Hospital of Greifswald, we can focus on the issues that are truly important for application in medicine.

futur: You mentioned the practical application of your research findings in clinical healthcare – that is the central idea of translational medicine. How do you ensure that these findings will actually be helping people?


We intend to turn the findings we obtain into a product through patent applications, for example an implant component. Working with medical device manufacturers, we can then launch this optimized product on the market in order to minimize infection rates or improve the ingrowth behavior of implants. This allows patients to benefit from our research in the long term. One other translational aspect is the preclinical method: For example, if we modify the implant surface in five different ways and observe in our experiments that a large quantity of aluminum is released by the implant in four of them, our analyses prevent us from proceeding to the preclinical phase or even to a clinical trial.

futur: Without the organ-on-a-chip systems, you would have to conduct your trials on animals. In your example, several mice would have been used to evaluate each of these different implant surfaces. Will we soon be able to discontinue such animal testing entirely?


It is my belief that we will not be able to abandon animal testing entirely. However, we will be able to perform more screening before proceeding on to animal studies. Animal testing will then only take place, if the product or drug being developed shows great potential for continuing on to the clinical phase. The greatest advantage with such 3D cultures and chip models is that we are working in a human context. An example: The chip system we are using within the consortium contains immune cells from bone marrow. The immune systems of a mouse that is kept sterile and a human are very different. We are dealing with cells from patients with an immunological history. If we use multiple chip systems with samples from multiple donors, we may also be including some that have already been sensitized to specific metals used in orthopedics. This is the only way that we can model a realistic setting for immune responses. For example, there are no mouse strains that exhibit specific immune responses to cobalt. Cells from different donors present the reality of patient variability, and it is precisely these patient-specific differences that are crucial.


The in vitro method is what makes the time-resolved measurement of the exact same sample possible in the first place. In the in vivo model, it would be necessary to kill the animals in order to examine the samples. On the organ- on-a-chip, on the other hand, we are able to continue culturing cells between the individual measurements in the CT. This is a unique aspect of this project, and one which could significantly expand the future relevance of the in vitro method.


With the help of organ-on-achip systems, we are also able to involve researchers from other disciplines. Many experts simply do not possess the infrastructure to work on animal models. I myself am not trained to perform experiments on mice. Finally, there is also a financial argument: It is more affordable for pharmaceutical or implant manufacturers to carry out such preliminary tests on chips. This means that they only conduct very expensive preclinical experiments on candidates that show real promise.


Glossar - Expert Discussion

Dr. Bernhard Hesse


performs the time-resolved μCT measurements at the synchrotron facility and evaluates the measurement results.

Dr. Janosch Schoon

Researcher at the orthopedics department of the University of the hospital of Greifswald in the research department Human Cells and Orthopedic Materials

cultivates human bone cells from patient samples. They are transferred onto microfluidic chips to study the interaction of the tissue with implants featuring different lasertextured surface structures and materials. 

Luiz G. De Souza Schweitzer

Researcher and Key Account Manager for medical engineering at the application center for microproduction technology at Fraunhofer IPK

is developing a measurement and transport unit which allows cell samples to be transferred reliably and in a sterile environment for measurement at the synchrotron facility and further cultivated on site over a period of several weeks.