title: In silico Mechano-Chemical Model of Bone Healing for the Regeneration of Critical Defects: The Effect of BMP-2.
abstract: 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.
authors.affiliation: IDMEC, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Frederico O
authors.initials: FO
authors.lastname: Ribeiro
authors.affiliation: Multiscale in Mechanical and Biological Engineering (M2BE), Aragón Institute of Engineering Research (I3A), University of Zaragoza, Zaragoza, Spain.
authors.forename: María José
authors.initials: MJ
authors.lastname: Gómez-Benito
authors.affiliation: IDMEC, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: João
authors.initials: J
authors.lastname: Folgado
authors.affiliation: IDMEC, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Paulo R
authors.initials: PR
authors.lastname: Fernandes
authors.affiliation: Multiscale in Mechanical and Biological Engineering (M2BE), Aragón Institute of Engineering Research (I3A), University of Zaragoza, Zaragoza, Spain.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: García-Aznar
mesh_terms: D000464:Alginates / Q000494:pharmacology; D000818:Animals; D001696:Biomechanical Phenomena / Q000187:drug effects; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology*; D001861:Bone Regeneration / Q000187:drug effects*; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D019902:Chondrocytes / Q000473:pathology; D003198:Computer Simulation; D020723:Glucuronic Acid / Q000494:pharmacology; D006603:Hexuronic Acids / Q000494:pharmacology; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000494:pharmacology; D006984:Hypertrophy; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D010012:Osteogenesis / Q000187:drug effects; D051381:Rats; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D000464:Alginates; D055396:Bone Morphogenetic Protein 2; D006603:Hexuronic Acids; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D020723:Glucuronic Acid