3D printed-matrix assisted chemically modified RNAs bone regenerative therapy for trauma and osteoporotic patients

Eu H2020
M Stoddart, A Banfi, C Plank, N Schepp, D Damien, F de Groot-Barrère, O Zelphati, O Fernandez, M van Griensven, J Amédée

Background

Mostly bone injuries heal successfully, however, there is an increasing number of cases where bone defects result in delayed healing or non-union. Current treatments such as autografting and bone graft substitutes containing growth factors have limitations, due to donor site morbidity and dose-related safety concerns, respectively. Additionally, current clinically available therapies lack control over spatial architecture to anatomically match defect sites. The cmRNAbone project aims to create a novel bone regenerative therapeutic approach, where biofabrication offers a great potential in producing patient-specific scaffolds that exhibit control over shape, architecture, and composition.

 

Goal

n this project a 3D-printable bone mimetic composite biomaterial-ink for bone regeneration is developed. This ink combines osteoinductive calcium phosphate particles (CaP) with tyramine modified hyaluronic acid (HA-Tyr) for the delivery of chemically modified RNAs (cmRNAs), to induce nerve, vessel, and bone formation (Figure). To achieve this aim, Semaphorin 3A (SEMA3a), Vascular endothelial growth factor (VEGF), Platelet-derived growth factor (PDGF-BB) and Bone Morphogenetic Protein-7 (BMP-7) cmRNAs targeting neurogenesis, vasculogenesis and osteogenesis will be synthesized, and delivered using vectors based on lipids and polysaccharide nanocapsules. A 3D printed HA-Tyr-CaP biomaterial-ink, that is customized to patient specific defect sites, will be loaded with the cmRNAs-vectors to release them and induce intrinsic osteoinductivity and guide sensory neurons and endothelial cells ingrowth for bone regeneration.


 

Results

Here, a 3D-printable ink was developed combining HA-Tyr with different sizes (45-63 and 45-106 ┬Ám) and concentrations (0, 10, 20 and 30% w/v) of CaP. All formulations were characterized by swelling, degradation and compression. The addition of CaP decreased the swelling, decreased the degradation rate and increased the compressive modulus. In order to increase cell attachment of human mesenchymal stromal cells (hMSCs), rat tail collagen type I (Col) was added to the ink and indeed resulted in increased cell viability and metabolic activity. Furthermore, preliminary results suggest increased alkaline phosphatase in the groups containing CaP, especially the group with the bigger size of CaP.


  • Publication
    van der Heide, D., Cidonio, G., Stoddart, M. J., D'Este, M. (2022). " 3D printing of inorganic biopolymer composites for bone regeneration". Biofabrication, 14, 042003.
  • Presentation

    van der Heide, D., Della Bella, E., Yuan, H., De Groot-Barrère, F., Stoddart, M. J., D'Este, M. (2022). "Natural bone inspired 3D printed composite biomaterial-ink composed of hyaluronan, collagen and calcium phosphate particles to promote bone regeneration". 8th Congress Graubünden forscht, Davos, Switzerland. Oral

    van der Heide, D., Della Bella, E., Yuan, H., De Groot-Barrère, F., Stoddart, M. J., D'Este, M. (2022). "Bone Mimetic Composite Biomaterial-Ink combining Hyaluronan, Collagen and Calcium Phosphate Particles for the Delivery of Chemically Modified RNA for Treatment of Bone Defects". 32nd Annual Conference of the European Society for Biomaterials, Bordeaux, France. Oral

    Matteo D'Este, Daphne van der Heide, Joëlle Amédée, Martin James Stoddart. cmRNAbone project: "3D Printed-Matrix Assisted Chemically Modified RNAs Bone Regenerative Therapy for Trauma and Osteoporotic Patients".  32nd Annual Conference of the European Society for Biomaterials, Bordeaux, France. Oral

    van der Heide, D., Della Bella, E., Yuan, H., De Groot-Barrère, F., Stoddart, M. J., D'Este, M. (2022). "Composite Biomaterial-Ink with Hyaluronan, Collagen and Calcium Phosphate Particles for Delivery of Chemically Modified RNA to promote Bone Regeneration". Tissue Engineering and Regenerative Medicine International Society (TERMIS) European Chapter Conference, Krakow, Poland. Oral

    van der Heide, D., Della Bella, E., Yuan, H., De Groot-Barrère, F., Stoddart, M. J., D'Este, M. (2022). "Bone resembling composite biomaterial-ink consisting of hyaluronan, collagen and calcium phosphate particles for bone regeneration". 26th Annual Meeting Swiss Society for Biomaterials + Regenerative Medicine (SSB+RM), Zürich, Switzerland. Poster

    van der Heide, D., Della Bella, E., Yuan, H., De Groot-Barrère, F., Stoddart, M. J., D'Este, M. (2021). "Biofabrication of bone graft substitutes using a composite biomaterial-ink based on hyaluronan and nano hydroxyapatite for delivering chemically modified RNAs". International Conference on Biofabrication, (Australia) online. Oral

    van der Heide, D., Della Bella, E., Yuan, H., De Groot-Barrère, F., Stoddart, M. J., D'Este, M. (2021). "Composite biomaterial-ink based on hyaluronan and nano hydroxyapatite for biofabrication of bone graft substitutes delivering chemically modified RNAs". 31st Annual Conference of the European Society for Biomaterials, (Porto, Portugal) online. Oral

    van der Heide, D., De Groot-Barrère, F., Stoddart, M. J., D'Este, M. (2021). "A Composite Biomaterial-Ink based on Hyaluronan and Nano Hydroxyapatite Delivering Chemically Modified RNA for Bone Regeneration".  6th World Congress of the Tissue Engineering and Regenerative Medicine International Society (TERMIS), (Maastricht, The Netherlands) online. Poster

    van der Heide, D., Stoddart, M. J., D'Este, M. (2021). "3D-Printed Matrix with Calcium Phosphate and Chemically Modified RNAs for Bone Regeneration of Trauma and Osteoporotic Patients". Swiss Young Researchers Network, online. Oral.

     

     

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