Bone Morphogenetic Protein 2 Induced Cellular Chemotaxis Drives Tissue Patterning During Critically Sized Bone Defect Healing: An <i>In silico</i> Study

AbstractCritical-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.

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Enhanced Bone Regeneration at a Segmental Bone Defect by Controlled Release of Bone Morphogenetic Protein-2 from a Biodegradable Hydrogel

Tissue Engineering ◽

10.1089/ten.2006.12.ft-68 ◽

2006 ◽

Vol 0 (0) ◽

pp. 060511071910001

Author(s):

Masaya Yamamoto ◽

Yoshitake Takahashi ◽

Yasuhiko Tabata

Keyword(s):

Controlled Release ◽

Bone Regeneration ◽

Bone Morphogenetic Protein ◽

Bone Defect ◽

Bone Morphogenetic Protein 2 ◽

Segmental Bone Defect ◽

Morphogenetic Protein ◽

Biodegradable Hydrogel ◽

Segmental Bone

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Cranial bone defect healing is accelerated by mesenchymal stem cells induced by coadministration of bone morphogenetic protein-2 and basic fibroblast growth factor

Wound Repair and Regeneration ◽

10.1111/j.1067-1927.2004.012118.x ◽

2004 ◽

Vol 12 (2) ◽

pp. 252-259 ◽

Cited By ~ 68

Author(s):

Sadanori Akita ◽

Masashi Fukui ◽

Hiroshi Nakagawa ◽

Tohru Fujii ◽

Kozo Akino

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Bone Morphogenetic Protein 2 ◽

Cranial Bone ◽

Fibroblast Growth ◽

Defect Healing ◽

Bone Defect Healing ◽

Morphogenetic Protein

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Heparin increases the osteogenic effect of recombinant human bone morphogenetic protein-2 in the rabbit bone defect model

Animal Cells and Systems ◽

10.1080/19768354.2015.1087429 ◽

2015 ◽

Vol 19 (5) ◽

pp. 312-320 ◽

Cited By ~ 3

Author(s):

Ju Yeon Ban ◽

Sang Wook Kang ◽

Gyeong-Ju Park

Keyword(s):

Bone Morphogenetic Protein ◽

Bone Defect ◽

Human Bone ◽

Bone Morphogenetic Protein 2 ◽

Defect Model ◽

Morphogenetic Protein ◽

Human Bone Morphogenetic Protein ◽

Rabbit Bone ◽

Osteogenic Effect ◽

Recombinant Human Bone

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Effect of Stromal Vascular Fraction on Fracture Healing with Bone Defects by Examination of Bone Morphogenetic Protein-2 Biomarkers in Murine Model

Open Access Macedonian Journal of Medical Sciences ◽

10.3889/oamjms.2021.7385 ◽

2021 ◽

Vol 9 (A) ◽

pp. 1132-1136

Author(s):

Respati S. Dradjat ◽

Panji Sananta ◽

Rizqi Daniar Rosandi ◽

Lasa Dhakka Siahaan

Keyword(s):

Bone Formation ◽

Bone Morphogenetic Protein ◽

Bone Defect ◽

Murine Model ◽

Healing Process ◽

Stromal Vascular Fraction ◽

Bone Defects ◽

The Body ◽

Bone Morphogenetic Protein 2 ◽

Morphogenetic Protein

BACKGROUND: Fractures and segmental bone defects are a significant cause of morbidity and a source of a high economic burden in healthcare. A severe bone defect (3 mm in murine model) is a devastating condition, which the bone cannot heal naturally despite surgical stabilization and usually requires further surgical intervention. The stromal vascular fraction (SVF) contains a heterogeneous collection of cells and several components, primarily: MSCs, HSCs, Treg cells, pericytic cells, AST cells, extracellular matrix, and complex microvascular beds (fibroblasts, white blood cells, dendritic cells, and intra-adventitial smooth muscular-like cells). Bone morphogenetic protein (BMP) is widely known for their important role in bone formation during mammalian development and confers a multifunctional role in the body, which has potential for therapeutic use. Studies have shown that BMPs play a role in the healing of large size bone defects. AIM: In this study, researchers aim to determine the effect of administering SVF from adipose tissue on the healing process of bone defects assessed based on the level biomarker of BMP-2. MATERIALS AND METHODS: This was an animal study involving 12 Wistar strain Rattus norvegivus. They were divided into three groups: Negative group (normal rats), positive group (rats with bone defect without SVF application), and SVF group (rats with bone defect with SVF application). After 30 days, the rats were sacrificed; the biomarkers that were evaluated are BMP-2. This biomarker was quantified using ELISA. RESULTS: BMP-2 biomarker expressions were higher in the SVF application group than in the group without SVF. All comparisons of the SVF group and positive control group showed significant differences (p = 0.026). CONCLUSION: SVF application could aid the healing process in a murine model with bone defect marked by the increased level of BMP-2 as a bone formation marker.

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