On the material side, we have developed a new injectable and printable hydrogel that includes ceramics, which can be used to 3D print new bone structures. We have also developed and installed in two laboratories the first prototype of a novel 3D printer that could be used in a clinical environment. To control the biology, we have developed chemically modified messenger RNA sequences that are able to express four therapeutic proteins which can be used to repair bone. These proteins naturally occur in patients during normal healing, so our aim is to give the body a helping hand by increasing the amount made in patients that do not have enough protein of their own. To be able to function correctly, these mRNA molecules must be able to get into cells within the body. Therefore, we are currently developing new reagents that enable the mRNA messenger to get into cells in the most efficient way and with the greatest safety profile. Thus, we have developed new gene transfer tools that will be both safe and efficient. We have shown the ability of these reagents to transfer the mRNA into cells, both in vitro and in vivo. We have defined the best mRNA carrier molecules, and tested the final composite, both under in a subcutaneous model to assess dose related changes and in 2 bone defect models. In this last stage of the project, the mRNA molecules were combined with the new printable bioink, using methods that allowed us to deliver the messages to the cells within the body in a 3D patient specific implant. We show that for some molecules, VEGF and NGF a low dose is most effective, while for BMP7 a high dose was more effective. We also have shown that despite the transient nature of the cmRNA expression, a long term effect could be observed. These results are currently being prepared for publication. Data from this project was used in a successful application to perform a proof of concept study in a large animal model, which is the final step prior to a first in human trial.
