![]() Furthermore, cell-free tubular composites of synthetic polymers and bone morphogenetic protein (BMP)-2 or BMP-7 15, 16, 17, 18 have been tested. Natural coral 10, 11, 12 and synthetic polymers 13, 14 have been investigated as tubular scaffold materials for mesenchymal stem cells (MSCs). ![]() Owing to the anatomy of the femoral diaphysis, studies have explored pre-formed tubular constructs in subcutaneous and orthotopic environments. Traditional scaffold-based bone tissue engineering approaches aim to create implantable constructs through a combination of biocompatible scaffolds, regeneration-competent cells, and/or bioactive cues 9. Postnatal bone retains the remarkable ability to heal via endochondral ossification without fibrous scarring 5, 6, 7 however, perturbations of the fracture site can interfere with the repair process when bone defects reach a critical size, which can contribute to non-union 8. This process is dependent on local morphogen gradients and mechanical forces in utero (reviewed in ref. Mesenchymal cell condensation in the early limb bud initiates long bone morphogenesis to form the cartilage anlage that gives rise to endochondral bone formation 2, 3. Long bones of the appendicular skeleton such as the femur provide load-bearing structure and carry out critical metabolic functions 1. This study demonstrates interactions between hMSC condensation geometry, morphogen bioavailability, and mechanical cues to recapitulate development for biomimetic bone tissue engineering. Tissue resembling normal growth plate was observed with negligible ectopic bone. Orthotopically, hMSC tubes stimulated more robust endochondral defect healing vs. Subcutaneously, hMSC tubes formed cartilage templates that underwent bony remodeling. Localized morphogen presentation stimulated chondrogenic priming/endochondral differentiation in vitro. Here, we hypothesized that localized presentation of transforming growth factor (TGF)-β1 and bone morphogenetic protein (BMP)-2 to engineered hMSC tubes mimicking femoral diaphyses induces endochondral ossification, and that TGF-β1 + BMP-2-presenting hMSC tubes enhance defect healing with delayed in vivo loading vs. Possible effects of construct geometry on healing outcome remain unclear. We recently showed functional restoration of femoral defects using scaffold-free human mesenchymal stem cell (hMSC) condensates featuring localized morphogen presentation with delayed in vivo mechanical loading. Biomimetic bone tissue engineering strategies partially recapitulate development.
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