3Rs-Centre Utrecht Life Sciences

Faculteit Dierengeneeskunde
October 2016
Promising 3D bio-printed bone marrow model provides new in vitro research possibilities

In the group of Bone Tissue Engineering within the Regenerative Medicine Program of the University Medical Center Utrecht (UMCU), dr. Jacqueline Alblas and her team are working on the development of a 3D bio-printed replica of human bone marrow. Not only has this research led to a new model that was not thought possible before; it also provided a base to start a collaboration to study the etiology and treatment of multiple myeloma. This new technique has the potential to replace many laboratory animals in studying bone-related diseases.

The Bone Tissue Engineering team has been using bio-printing techniques for about 10 years now1. Their aim is to develop hybrid constructs in which cell function and viability are preserved. These bone-replacing constructs may substitute autologous bone surgeries in humans, which are invasive and often inadequate. While optimizing this bio-printed bone model2, Albas’ team got into contact with the Hematology group at the Hubrecht Institute, which studies the development of multiple myeloma; a form of cancer that features weakening of the bones. The malignant cells seem to induce permanent changes in the bone, even when the tumor has been removed entirely. Previously, it was hard to study this feature ex vivo since multiple myeloma cells are not viable outside the bone marrow. Therefore, the two teams started a collaboration in which they used the new knowledge of bone tissue engineering to construct a model reminiscent of bone marrow. By doing this, the researchers found a way to study the natural processes in these malignant cells in vitro. By combining different components of both bone marrow and bone itself,3 they constructed a bone marrow model in which tumor cells extracted from patients can function, divide and be kept alive for four weeks. Consequently, this opens many doors for new in vitro research opportunities.

The perks of in vitro research compared to an animal model
In traditional bone tissue engineering, a bone matrix-like implant is inserted in a mouse after adding humane mesenchymal stem cells (MSCs). However, the use of this mouse model has a lot of downsides, according to Alblas. Apart from the ethical considerations of using animals for research, keeping the animals is expensive and time-consuming. Since variation is likely to occur in these kind of studies, a large number of animals are needed in order to get a reliable result. Another important factor is the fact that the mouse model used is immune deficient, in order to avoid rejection of the human cells, and thus interactions with the immune system cannot be studied. In line with this, results are obtained in a mouse environment and are therefore not easily translatable to the human situation.
A huge advantage of this new 3D bio-printed in vitro method is that human cells are used and that the parameters and environment within the experiment can be controlled, thereby to minimizing variation and maximizing control.

Enthusiasm in other fields
Within the field of regenerative medicine, many groups are trying to make a similar model as ours, says Alblas. Therefore, people respond enthusiastically every time we present our results. Scientists from other fields come to us as well. For example, the Oncology department is looking for ways to replicate lymphatic vessels. We can provide them with knowledge on 3D bio-printing techniques to help them reach their scientific goals. Undoubtedly, there are many possibilities for other researchers out there to explore these new in vitro possibilities, thereby tremendously reducing the number of animals used in research. Unfortunately, we are still not able to replicate the complexity of a whole organism, but with 3D bio-printing techniques we can make more complex replicas and therefore complete more steps in our study without using animals.
This interdisciplinary study was financed by a Seed Grant4 from Utrecht University, which dr. Alblas received together with her colleague Catherine Robin from the Hubrecht Institute1. The paper that provides fascinating outcomes from the multiple myeloma study will be sent in for publication shortly.

Catherine Robin and Jacqueline Alblas

  1. Fedorovich NE, Alblas J, Hennink WE, Oner FC, Dhert WJ. (2011) Organ printing: the future of bone regeneration? Trends in Biotechnology 29(12):601-606.
  2. E. Fedorovich, E. Kuipers, D. Gawlitta, W.J. Dhert, J. Alblas (2011) Scaffold porosity and oxygenation of printed hydrogel constructs affect functionality of embedded osteogenic progenitors. Tissue Engineering Part A(17):2473–2486.
  3. The paper providing details on which components made the bone marrow viable will be sent in for publication soon.
  4. Read more about the Seed Grant here: http://www.uu.nl/en/news/researchers-replicate-natural-bone-marrow.