title: Local Controlled Release of Polyphenol Conjugated with Gelatin Facilitates Bone Formation.
abstract: Catechins are extensively used in health care treatments. Nevertheless, there is scarce information about the feasibility of local administration with polyphenols for bone regeneration therapy, possibly due to lack of effective delivery systems. Here we demonstrated that the epigallocatechin-3-gallate-conjugated gelatin (EGCG/Gel) prepared by an aqueous chemical synthesis using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-morpholinium chloride (DMT-MM) gradually disintegrated with time and facilitated bone formation in a critical size defect of a mouse calvaria. Conjugation of EGCG with the Gel generated cross-linking between the two molecules, thereby leading to a retardation of the degradation of the EGCG/Gel and to a delayed release of EGCG. The prepared EGCG/Gels represented significant osteogenic capability compared with that of the uncross-linked Gel and the cross-linked Gel with uncombined-EGCG. In vitro experiments disclosed that the EGCG/Gel induced osteoblastogenesis of a mouse mesenchymal stem cell line (D1 cells) within 14 days. Using fluorescently-labeled EGCG/Gel, we found that the fraction of EGCG/Gel adsorbed onto the cell membrane of the D1 cells possibly via a Gel-cell interaction. The interaction might confer the long-term effects of EGCG on the cells, resulting in a potent osteogenic capability of the EGCG/Gel in vivo. These results should provide insight into local controlled release of polyphenols for bone therapy.
authors.affiliation: Institute of Dental Research, Osaka Dental University, 8-1 Kuzuhahanazonocho, Hirakata, Osaka 573-1121, Japan. honda-y@cc.osaka-dent.ac.jp.
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Honda
authors.affiliation: Graduate School of Science and Technology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan. t-tanaka@kit.ac.jp.
authors.forename: Tomonari
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Department of Orthodontics, Osaka Dental University, 8-1, Kuzuhahanazonocho, Hirakata, Osaka 573-1121, Japan. tocco.tmk.26@gmail.com.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Tokuda
authors.affiliation: Department of Oral Implantology, Osaka Dental University; 8-1 Kuzuhahanazonocho, Hirakata, Osaka, 573-1121, Japan. kasiwagi@cc.osaka-dent.ac.jp.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kashiwagi
authors.affiliation: Department of Oral Implantology, Osaka Dental University; 8-1 Kuzuhahanazonocho, Hirakata, Osaka, 573-1121, Japan. kaida-k@cc.osaka-dent.ac.jp.
authors.forename: Koji
authors.initials: K
authors.lastname: Kaida
authors.affiliation: Department of Oral Implantology, Osaka Dental University; 8-1 Kuzuhahanazonocho, Hirakata, Osaka, 573-1121, Japan. hieda-a@cc.osaka-dent.ac.jp.
authors.forename: Ayato
authors.initials: A
authors.lastname: Hieda
authors.affiliation: Department of Oral Implantology, Osaka Dental University; 8-1 Kuzuhahanazonocho, Hirakata, Osaka, 573-1121, Japan. umezaki@cc.osaka-dent.ac.jp.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Umezaki
authors.affiliation: Osaka Dental University; 8-1 Kuzuhahanazonocho, Hirakata, Osaka 573-1121, Japan. yoshiya@cc.osaka-dent.ac.jp.
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Hashimoto
authors.affiliation: Osaka Dental University; 8-1 Kuzuhahanazonocho, Hirakata, Osaka 573-1121, Japan. imai@cc.osaka-dent.ac.jp.
authors.forename: Koichi
authors.initials: K
authors.lastname: Imai
authors.affiliation: Department of Orthodontics, Osaka Dental University, 8-1, Kuzuhahanazonocho, Hirakata, Osaka 573-1121, Japan. naoyuki@cc.osaka-dent.ac.jp.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Matsumoto
authors.affiliation: Department of Oral Implantology, Osaka Dental University; 8-1 Kuzuhahanazonocho, Hirakata, Osaka, 573-1121, Japan. baba-s@cc.osaka-dent.ac.jp.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Baba
authors.affiliation: Institute of Dental Research, Osaka Dental University, 8-1 Kuzuhahanazonocho, Hirakata, Osaka 573-1121, Japan. shimizu@cc.osaka-dent.ac.jp.|Department of Oral Radiology, Osaka Dental University, 8-1 Kuzuhahanazonocho, Hirakata, Osaka 573-1121, Japan. shimizu@cc.osaka-dent.ac.jp.
authors.forename: Kimishige
authors.initials: K
authors.lastname: Shimizutani
mesh_terms: D000818:Animals; D002392:Catechin / Q000031:analogs & derivatives* / Q000737:chemistry; D002454:Cell Differentiation / Q000187:drug effects; D003692:Delayed-Action Preparations; D005780:Gelatin / Q000737:chemistry*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology*; D059808:Polyphenols / Q000494:pharmacology*; D012886:Skull / Q000187:drug effects / Q000473:pathology*
chemical_list: D003692:Delayed-Action Preparations; D059808:Polyphenols; D002392:Catechin; D005780:Gelatin; C045651:epigallocatechin gallate
keywords: EGCG; bone formation; catechin; gelatin; mesenchymal stem cells