Periodic Reporting for period 3 - cmRNAbone (3D Printed-Matrix Assisted Chemically Modified RNAs Bone Regenerative Therapy for Trauma and Osteoporotic Patients)
Okres sprawozdawczy: 2023-01-01 do 2024-06-30
After an accident, it is possible a patient might have broken a bone. As people live longer and healthier active lives, the number of elderly patients with osteoporosis that then have a fall leading to a fracture is increasing. As people get older, the potential for complications after a fracture increases and the risk that the bone does not heal properly is further increased if the patient has osteoporosis. This means new tools and therapies need to be developed to help this growing group of patients.
The cmRNAbone project developed new materials and treatments to potentially improve bone regeneration in osteoporotic patients. To enable the materials to be more patient specific, we are able to 3D print the implant using a novel 3D printer that was developed by the team. We are also combined bone line particles made of ceramic into a bioink that can deliver the therapeutic and will work perfectly with the new printer. The way bones heal is dependent both on the mechanical environment and on the underlying biology. Therefore, the bioink developed is able to mechanically support the loads applied across a fracture gap. After the coronavirus pandemic, many people are more aware of the potential for messenger RNA (mRNA) molecules to produce proteins in the body, as this forms the basis of some of the new coronavirus vaccines. The mRNA message carries the recipe for proteins, allowing cell to make the protein of interest. After some days, the mRNA has done its job and will be broken down by the body, leaving no permanent changes. Within the cmRNAbone project, we have used mRNA to produce proteins that will enhance the healing response that is naturally occurring within the patient.
Therefore, this project has lead to 3D printable patient specific implants, that can deliver messages on how to make additional proteins to boost the bodies own healing response.
The cmRNAbone project developed new materials and treatments to potentially improve bone regeneration in osteoporotic patients. To enable the materials to be more patient specific, we are able to 3D print the implant using a novel 3D printer that was developed by the team. We are also combined bone line particles made of ceramic into a bioink that can deliver the therapeutic and will work perfectly with the new printer. The way bones heal is dependent both on the mechanical environment and on the underlying biology. Therefore, the bioink developed is able to mechanically support the loads applied across a fracture gap. After the coronavirus pandemic, many people are more aware of the potential for messenger RNA (mRNA) molecules to produce proteins in the body, as this forms the basis of some of the new coronavirus vaccines. The mRNA message carries the recipe for proteins, allowing cell to make the protein of interest. After some days, the mRNA has done its job and will be broken down by the body, leaving no permanent changes. Within the cmRNAbone project, we have used mRNA to produce proteins that will enhance the healing response that is naturally occurring within the patient.
Therefore, this project has lead to 3D printable patient specific implants, that can deliver messages on how to make additional proteins to boost the bodies own healing response.
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.
3D printing has a huge potential to design new implants specifically for each patient, and for each fractured bone. The printer have developed will enable this technology to be used within the clinics. The new mRNA delivery agents will increase the potential of clinical translation. Combining the printer with the new bioink and the control of the underlying biology will greatly improve patient care and allow for bone healing in situations where it is currently not possible. This will allow patients to remain mobile and active, which has known health benefits. Having demonstrated regenerative potential for the cmRNA platform beyond its well known role in vaccines, the low cost of the approach combined with the infrastructure for mRNA vaccines being in place after COVID, greatly increases the potential this technology can be applied therapeutically.