In silico Mechano-Chemical Model of Bone Healing for the Regeneration of Critical Defects: The Effect of BMP-2

• Published in: PloS one 2015-06, Vol.10 (6), p.e0127722
• Main Authors: Ribeiro, Frederico O, Gómez-Benito, María José, Folgado, João, Fernandes, Paulo R, García-Aznar, José Manuel
• Format: Article
• Language: English
• Subjects: Alginates - pharmacology; Analysis; Animals; Biocompatibility; Bioengineering; Biomechanical Phenomena - drug effects; Biomechanics; Biomedical materials; Bone and Bones - drug effects; Bone and Bones - pathology; Bone growth; Bone healing; Bone morphogenetic protein 2; Bone Morphogenetic Protein 2 - pharmacology; Bone morphogenetic proteins; Bone Regeneration - drug effects; Bones; Cell Proliferation - drug effects; Cellular manufacture; Chemical stimuli; Chemotaxis - drug effects; Chondrocytes - pathology; Computer Simulation; Defects; Engineering research; Extracellular matrix; Fractures; Glucuronic Acid - pharmacology; Growth factors; Healing; Hexuronic Acids - pharmacology; Hydrogel, Polyethylene Glycol Dimethacrylate - pharmacology; Hydrogels; Hypertrophy; Mathematical models; Mechanical properties; Medical equipment; Medical research; Mesenchymal Stem Cells - cytology; Mesenchymal Stem Cells - drug effects; Mesenchymal Stem Cells - metabolism; Models, Biological; Osteogenesis; Osteogenesis - drug effects; Proteins; Rats; Regeneration; Shear strain; Surgical implants; Tissue engineering; Tomography; Wound Healing - drug effects
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0127722

The healing of bone defects is a challenge for both tissue engineering and modern orthopaedics. This problem has been addressed through the study of scaffold constructs combined with mechanoregulatory theories, disregarding the influence of chemical factors and their respective delivery devices. Of the chemical factors involved in the bone healing process, bone morphogenetic protein-2 (BMP-2) has been identified as one of the most powerful osteoinductive proteins. The aim of this work is to develop and validate a mechano-chemical regulatory model to study the effect of BMP-2 on the healing of large bone defects in silico. We first collected a range of quantitative experimental data from the literature concerning the effects of BMP-2 on cellular activity, specifically proliferation, migration, differentiation, maturation and extracellular matrix production. These data were then used to define a model governed by mechano-chemical stimuli to simulate the healing of large bone defects under the following conditions: natural healing, an empty hydrogel implanted in the defect and a hydrogel soaked with BMP-2 implanted in the defect. For the latter condition, successful defect healing was predicted, in agreement with previous in vivo experiments. Further in vivo comparisons showed the potential of the model, which accurately predicted bone tissue formation during healing, bone tissue distribution across the defect and the quantity of bone inside the defect. The proposed mechano-chemical model also estimated the effect of BMP-2 on cells and the evolution of healing in large bone defects. This novel in silico tool provides valuable insight for bone tissue regeneration strategies.