title: Enhancement of bone regeneration by dual release of a macrophage recruitment agent and platelet-rich plasma from gelatin hydrogels.
abstract: Macrophages play an important role in regulating inflammatory responses and tissue regeneration. In the present study, their effect on bone remodeling is investigated by the simultaneous application of a macrophage recruiting agent, SEW2871 of a sphingosine-1 phosphate agonist, and platelet-rich plasma (PRP). The non-water soluble SEW2871 was solubilized in water through micelles formation with l-lactic acid grafted gelatin, and the resulting micelles with PRP were incorporated into gelatin hydrogels. Mixed SEW2871-micelles and PRP were released from gelatin hydrogels in a controlled fashion both in vitro and in vivo. In vitro migration assay revealed that the presence of PRP synergistically promoted SEW2871-induced macrophages migration. When applied to a bone defect of rats, the hydrogels incorporating mixed SEW2871-micelles and PRP recruited a higher number of macrophages than those hydrogels incorporating either SEW2871-micelles or PRP. The hydrogels incorporating mixed SEW2871-micelles and PRP enhanced the level of tumor necrosis factor (TNF)-α of pro-inflammatory cytokine, 3 days after application, while pro-inflammatory responses coupled with a significant increase in the expression level of osteoprotegerin (OPG) and interleukin (IL)-10 and transforming growth factor (TGF)-β1 of anti-inflammatory cytokine were observed 10 days postoperatively. The hydrogels incorporating mixed SEW2871-micelles and PRP promoted bone regeneration to a significant great extent compared with those incorporating PBS and either SEW2871-micelles or PRP. It is concluded that macrophages recruitment contributed to PRP-induced bone regeneration.
authors.affiliation: Department of Biomaterials, Field of Tissue Engineering, Institute for Frontier Medical Sciences, Kyoto University, 53 Kawara-cho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Yang-Hee
authors.initials: YH
authors.lastname: Kim
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Furuya
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tabata
mesh_terms: D000818:Animals; D001861:Bone Regeneration; D001842:Bone and Bones / Q000378:metabolism; D002465:Cell Movement; D016207:Cytokines / Q000378:metabolism; D005780:Gelatin; D020100:Hydrogels; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000166:cytology*; D053244:Osteoprotegerin / Q000378:metabolism; D053657:Platelet-Rich Plasma; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D016207:Cytokines; D020100:Hydrogels; D018836:Inflammation Mediators; D053244:Osteoprotegerin; D005780:Gelatin
keywords: Bone regeneration; Controlled release; Gelatin hydrogel; Macrophages; Platelet rich plasma (PRP); S1P(1) agonist (SEW2871)