title: Quantitative, structural, and image-based mechanical analysis of nonunion fracture repaired by genetically engineered mesenchymal stem cells.
abstract: Stem cell-mediated gene therapy for fracture repair, utilizes genetically engineered mesenchymal stem cells (MSCs) for the induction of bone growth and is considered a promising approach in skeletal tissue regeneration. Previous studies have shown that murine nonunion fractures can be repaired by implanting MSCs over-expressing recombinant human bone morphogenetic protein-2 (rhBMP-2). Nanoindentation studies of bone tissue induced by MSCs in a radius fracture site indicated similar elastic modulus compared to intact murine bone, eight weeks post-treatment. In the present study we sought to investigate temporal changes in microarchitecture and biomechanical properties of repaired murine radius bones, following the implantation of MSCs. High-resolution micro-computed tomography (micro-CT) was performed 10 and 35 weeks post MSC implantation, followed by micro-finite element (micro-FE) analysis. The results have shown that the regenerated bone tissue remodels over time, as indicated by a significant decrease in bone volume, total volume, and connectivity density combined with an increase in mineral density. In addition, the axial stiffness of limbs repaired with MSCs was 2-1.5 times higher compared to the contralateral intact limbs, at 10 and 35 weeks post-treatment. These results could be attributed to the fusion that occurred in between the ulna and radius bones. In conclusion, although MSCs induce bone formation, which exceeds the fracture site, significant remodeling of the repair callus occurs over time. In addition, limbs treated with an MSC graft demonstrated superior biomechanical properties, which could indicate the clinical benefit of future MSC application in nonunion fracture repair.
authors.affiliation: Skeletal Biotech Laboratory, The Hebrew University-Hadassah Faculty of Dental Medicine, PO Box 12272, Ein Kerem, Jerusalem 91120, Israel.
authors.forename: Ilan
authors.initials: I
authors.lastname: Kallai
authors.forename: G Harry
authors.initials: GH
authors.lastname: van Lenthe
authors.forename: Davide
authors.initials: D
authors.lastname: Ruffoni
authors.forename: Yoram
authors.initials: Y
authors.lastname: Zilberman
authors.forename: Ralph
authors.initials: R
authors.lastname: Müller
authors.forename: Gadi
authors.initials: G
authors.lastname: Pelled
authors.forename: Dan
authors.initials: D
authors.lastname: Gazit
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D015519:Bone Density; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics; D001861:Bone Regeneration; D016723:Bone Remodeling; D004195:Disease Models, Animal; D055119:Elastic Modulus; D005260:Female; D020342:Finite Element Analysis; D005599:Fractures, Ununited / Q000000981:diagnostic imaging / Q000503:physiopathology / Q000628:therapy*; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D011885:Radius Fractures / Q000000981:diagnostic imaging / Q000503:physiopathology / Q000628:therapy; D011994:Recombinant Proteins / Q000235:genetics; D055114:X-Ray Microtomography
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D011994:Recombinant Proteins
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