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.
Highlights
The repair of critical size bone fractures is an important challenge facing modern orthopedics researchers
We present the following results: (1) based on the argument that bone morphogenetic protein-2 (BMP-2) is one of the most important growth factors involved in bone fracture healing [21,45,46,47], we collected quantitative data on the effects of bone morphogenetic proteins (BMPs)-2 on cell proliferation, migration, differentiation, maturation and extracellular matrix (ECM) production (2) the effects of BMP-2 on cells were incorporated into a mechanoregulatory model, combining and integrating mechanical and biological stimuli [48] and (3) we defined a mechano-chemical model to simulate healing of a critical size fracture with a hydrogel incorporated as a BMP-2 delivering device
We focused on BMP-2 because it is considered by many authors to be one of the most important growth factors for bone healing [45,47] and bone tissue regeneration [14,15]
Summary
The repair of critical size bone fractures is an important challenge facing modern orthopedics researchers. The gold standard procedure for critical size defect repair consists of filling the defect with autografted bone harvested from the iliac crest [1]. In addition to the PLOS ONE | DOI:10.1371/journal.pone.0127722. In Silico Model of Bone Healing: The Effect of BMP-2. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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