Agent-based model; Bone defect healing; Bone morphogenetic protein 2; Finite element analysis; Mechanobiology; BMP2 protein, human; Bone Morphogenetic Protein 2; Recombinant Proteins; Transforming Growth Factor beta; recombinant human bone morphogenetic protein-2; Collagen; Animals; Bone Morphogenetic Protein 2/chemistry; Bone Regeneration/drug effects; Bony Callus; Cell Differentiation; Chemotaxis/drug effects; Collagen/chemistry; Computer Simulation; Femur/drug effects; Finite Element Analysis; Humans; In Vitro Techniques; Mesenchymal Stem Cells/metabolism; Osteogenesis/drug effects; Rats; Recombinant Proteins/chemistry; Risk; Transforming Growth Factor beta/chemistry; Wound Healing/physiology; X-Ray Microtomography; Biological principles; Bone morphogenetic proteins; Bone tissue formation; Computational model; Mesenchymal stromal cells; Spatial and temporal distribution; Specific concentration; Bone Regeneration; Chemotaxis; Femur; Mesenchymal Stem Cells; Osteogenesis; Wound Healing; Biotechnology; Modeling and Simulation; Mechanical Engineering
Abstract :
[en] Critical-sized bone defects are critical healing conditions that, if left untreated, often lead to non-unions. To reduce the risk, critical-sized bone defects are often treated with recombinant human BMP-2. Although enhanced bone tissue formation is observed when BMP-2 is administered locally to the defect, spatial and temporal distribution of callus tissue often differs from that found during regular bone healing or in defects treated differently. How this altered tissue patterning due to BMP-2 treatment is linked to mechano-biological principles at the cellular scale remains largely unknown. In this study, the mechano-biological regulation of BMP-2-treated critical-sized bone defect healing was investigated using a multiphysics multiscale in silico approach. Finite element and agent-based modeling techniques were combined to simulate healing within a critical-sized bone defect (5 mm) in a rat femur. Computer model predictions were compared to in vivo microCT data outcome of bone tissue patterning at 2, 4, and 6 weeks postoperation. In vivo, BMP-2 treatment led to complete healing through periosteal bone bridging already after 2 weeks postoperation. Computer model simulations showed that the BMP-2 specific tissue patterning can be explained by the migration of mesenchymal stromal cells to regions with a specific concentration of BMP-2 (chemotaxis). This study shows how computational modeling can help us to further understand the mechanisms behind treatment effects on compromised healing conditions as well as to optimize future treatment strategies.
Disciplines :
Engineering, computing & technology: Multidisciplinary, general & others
Author, co-author :
Borgiani, Edoardo ; Julius Wolff Institute, Berlin Institute of Health, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum, Institutsgebäude Süd/ Südstraße 2, Augustenburger Platz 1, 13353, Berlin, Germany
Duda, Georg N; Julius Wolff Institute, Berlin Institute of Health, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum, Institutsgebäude Süd/ Südstraße 2, Augustenburger Platz 1, 13353, Berlin, Germany
Willie, Bettina M ; Research Centre, Department of Pediatric Surgery, Shriners Hospital for Children-Canada, McGill University, 1003 Decarie Blvd, Montreal, QC, H4A 0A9, Canada
Checa, Sara ; Julius Wolff Institute, Berlin Institute of Health, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum, Institutsgebäude Süd/ Südstraße 2, Augustenburger Platz 1, 13353, Berlin, Germany. sara.checa@charite.de
Language :
English
Title :
Bone morphogenetic protein 2-induced cellular chemotaxis drives tissue patterning during critical-sized bone defect healing: an in silico study.
Publication date :
August 2021
Journal title :
Biomechanics and Modeling in Mechanobiology
ISSN :
1617-7959
eISSN :
1617-7940
Publisher :
Springer Science and Business Media Deutschland GmbH, Germany
DFG - Deutsche Forschungsgemeinschaft [DE] Charité - Universitätsmedizin Berlin [DE]
Funding text :
Open Access funding enabled and organized by Projekt DEAL. This study was funded by the German Research Foundation [Deutsche Forschungsgemeinschaft; WI 3761/4‐1, DU298/14‐1; CH 1123/4‐1]. Bettina M. Willie receives supported from Shriners Hospital for Children and the FRQS Programme de bourses de chercheur.
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