Exposome-on-a-chip: eliminating the elusiveness of the flavonoid hesperidin effect on bone and BMP function

Abstract Bone morphogenetic protein as a bone regeneration biologic has experienced steady decline in use given its side effects. Our published work has shown, for the first time, that a natural compound, dietary hesperidin (HE), can control BMP side effects likely via multiple mechanisms. These include control of inflammation, osteogenesis and osteocyte function in regenerated and native mandible bone. Due to the complexities of the multifactorial effect of phytochemicals such as HE, a multi-cellular system mimicking the bone environment would be an ideal ex-vivo setting for undertaking mechanistic studies to understand its role on BMP function and craniofacial bone. Such system could be targeted to simulate the mechanics of the bone environment given specific shear stresses. Based on preliminary data, it is our hypothesis that HE limits inflammation induced by exogenous BMP2 via TLR receptors, and that it can promote new high-quality bone formation via its modulation of osteoblast-osteocyte interaction, promoting BMP signaling, favoring fast matrix remodeling and Ca2+ deposition. Further, this grant proposes the utilization of an innovative 3D co-culture platform which will facilitate the understanding of the effect of the bone exposome containing HE +/- BMP on bone cells and allow data collection in a bone network set to mimic the microenvironment. This proposal is in response to the NIH RFA DE-025-002 which will support the validation of novel dental, oral and craniofacial (DOC) organ-on-a-chip (OoC). The proposal offers high reward since, if successful, will provide further understanding of BMP2 function in bone regeneration, a novel approach on modulation of BMP2 via phytochemicals and ultimately, provide validation of a new 3D bone culture system mimicking the bone cell interactions under mandible-like mechanics (frequent shear stresses) (the OoC). The results can be compared to our previous pre-clinical studies and ultimately the proposed bone exposome-on-a-chip may offer validation, equivalence and perhaps outperform animal testing.