Engineering of Bone Substitutes
1. Mesenchymal stromal cells and developmental engineering
The golden standard for the treatment of critical bone defects is the use of autologous bone, although this is associated with high donor site morbidity. The use of MSCs from the bone marrow has been proposed to generate osteogenic grafts, but the efficiency and reproducibility has not been convincing. Based on the hypothesis that the robustness of the process could be increased by mimicking bone embryonic development, we generated intermediate templates consisting of hypertrophic cartilage that – upon in vivo implantation – have the capacity to autonomously remodel into bone tissue and thereby recapitulate the events occurring during endochondral ossification. The same remodeling can also be achieved with tissue engineered decellularized constructs where the cocktail of factors necessary to initiate the process is embedded in the previously deposited extracellular matrix.
Scotti C et al. Recapitulation of endochondral bone formation using human adult mesenchymal stem cells as a paradigm for developmental engineering. Proc Natl Acad Sci USA, 2010. Pubmed.
Osinga R et al. Generation of a Bone Organ by Human Adipose-Derived Stromal Cells Through Endochondral Ossification. Stem Cells Transl Med, 2016. Pubmed.
Papadimitropoulos A et al. Engineered decellularized matrices to instruct bone regeneration processes. Bone, 2015. Pubmed.
2. Adipose-derived cells and engineering of osteogenic/vasculogenic grafts
Mesenchymal stromal cells are also found within the Stromal Vascular Fraction (SVF) of adipose tissue, in conjunction with endothelial lineage cells. These SVF-cells have the capacity to self-assemble into osteogenic and vasculogenic structures upon orthotopic implantation and been used previously in an intraoperative approach in a clinical trial to enhance fracture healing. Biopsies taken at the repair site upon plate removal indicate the formation of de novo bone tissue throughout the implant site, as opposed to osteoconduction from the existing bone, thus strongly suggesting osteogenesis by the grafted cells. Studies are ongoing to combine the strategy of engineered and decellularized matrices presented in the previous section with the use of SVF cells to intraoperatively “re-activate” such constructs in order to enhance bone and vascular development. A first case study is ongoing where SVF cells are combined with a bone substitute material for the partial reconstruction of an upper jaw.
Ismail T et al. Engineered, axially-vascularized osteogenic grafts from human adipose-derived cells to treat avascular necrosis of bone in a rat model. Acta Biomater, 2017. Pubmed.
Saxer F and Scherberich A et al. Implantation of Stromal Vascular Fraction Progenitors at Bone Fracture Sites: From a Rat Model to a First-in-Man Study. Stem Cells, 2016. Pubmed.
Scherberich A et al. Three-dimensional perfusion culture of human adipose tissue-derived endothelial and osteoblastic progenitors generates osteogenic constructs with intrinsic vascularization capacity. Stem Cells, 2007. Pubmed.
3. In vivo imaging of engineered tissue
The detection and quantification of bone formation and vessel ingrowth in engineered osteogenic grafts in vivo remains a critical issue in bone tissue engineering. To address these unmet needs, we investigate the use of state-of-the-art imaging techniques including: tomography, magnetic resonance with or without contrast agents, and intra-vital staining coupled to two-photon microscopy.
Sutter S et al. Contrast-Enhanced Microtomographic Characterisation of Vessels in Native Bone and Engineered Vascularised Grafts Using Ink-Gelatin Perfusion and Phosphotungstic Acid. Contrast Media Mol Imaging, 2017. Pubmed.
Jalili-Firoozinezhad S et al. Bimodal morphological analyses of native and engineered tissues. Mater Sci Eng Matter Biol Appl, 2017. Pubmed.
- EU INTERREG Rhin Supérieur/Oberrhein / Swiss Confederation / Cantons BL BS AG, Interreg V, Projekt Nr. 41: NANOTRANSMED, Innovations en Nanomédecine: du diagnostic à l'implantologie/Innovationen in der Nanomedizin: von der Diagnose zur Implantologie