Journal
BIOMATERIALS
Volume 33, Issue 33, Pages 8265-8276Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2012.07.041
Keywords
Bone tissue engineering; Bone remodeling; Cytokine combination therapy; Systems biology; Osteogenic differentiation; Signaling pathway
Funding
- NIH [R01LM010185-03, U01HL111560-01, 1R01DE022676-01]
- [Uo1 CA166886-01]
- [DODW81XWH-11-2-0168-P4]
- [DODW81XWH-10-1-0966]
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The long-term performance of tissue-engineered bone grafts is determined by a dynamic balance between bone regeneration and resorption. We proposed using embedded cytokine slow-releasing hydrogels to tune this balance toward a desirable final bone density. In this study we established a systems biology model, and quantitatively explored the combinatorial effects of delivered cytokines from hydrogels on final bone density. We hypothesized that: 1) bone regeneration was driven by transcription factors Runx2 and Osterix, which responded to released cytokines, such as Wnt, BMP2, and TGF beta, drove the development of osteoblast lineage, and contributed to bone mass generation; and 2) the osteoclast lineage, on the other hand, governed the bone resorption, and communications between these two lineages determined the dynamics of bone remodeling. In our model. Intracellular signaling pathways were represented by ordinary differential equations, while the intercellular communications and cellular population dynamics were modeled by stochastic differential equations. Effects of synergistic cytokine combinations were evaluated by Loewe index and Bliss index. Simulation results revealed that the Wnt/BMP2 combinations released from hydrogels showed best control of bone regeneration and synergistic effects, and suggested optimal dose ratios of given cytokine combinations released from hydrogels to most efficiently control the long-term bone remodeling. We revealed the characteristics of cytokine combinations of Wnt/BMP2 which could be used to guide the design of in vivo bone scaffolds and the clinical treatment of some diseases such as osteoporosis. (C) 2012 Elsevier Ltd. All rights reserved.
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