title: Controlled release of simvastatin from in situ forming hydrogel triggers bone formation in MC3T3-E1 cells.
abstract: Simvastatin (SIM), a drug commonly administered for the treatment of hypercholesterolemia, has been recently reported to induce bone regeneration/formation. In this study, we investigated the properties of hydrogel composed of gelatin-poly(ethylene glycol)-tyramine (GPT) as an efficient SIM delivery vehicle that can trigger osteogenic differentiation. Sustained delivery of SIM was achieved through its encapsulation in an injectable, biodegradable GPT-hydrogel. Cross-linking of the gelatin-based GPT-hydrogel was induced by the reaction of horse radish peroxidase and H(2)O(2). GPT-hydrogels of three different matrix stiffness, 1,800 (GPT-hydrogel1), 5,800 (GPT-hydrogel2), and 8,400 Pa (GPT-hydrogel3) were used. The gelation/degradation time and SIM release profiles of hydrogels loaded with two different concentrations of SIM, 1 and 3 mg/ml, were also evaluated. Maximum swelling times of GPT-hydrogel1, GPT-hydrogel2, and GPT-hydrogel3 were observed to be 6, 12, and 20 days, respectively. All GPT-hydrogels showed complete degradation within 55 days. The in vitro SIM release profiles, investigated in PBS buffer (pH 7.4) at 37°C, exhibited typical biphasic release patterns with the initial burst being more rapid with GPT-hydrogel1 compared with GPT-hydrogel3. Substantial increase in matrix metalloproteinase-13, osteocalcin expression levels, and mineralization were seen in osteogenic differentiation system using MC3T3-E1 cells cultured with GPT-hydrogels loaded with SIM in a dose-dependent manner. This study demonstrated that controlled release of SIM from a biodegradable, injectable GPT-hydrogel had a promising role for long-term treatment of chronic degenerative diseases such as disc degenerative disease.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, The University of Michigan, 428 Church Street, Ann Arbor, MI 48109-1065, USA.
authors.forename: Yoon Shin
authors.initials: YS
authors.lastname: Park
authors.forename: Allan E
authors.initials: AE
authors.lastname: David
authors.forename: Kyung Min
authors.initials: KM
authors.lastname: Park
authors.forename: Chia-Ying
authors.initials: CY
authors.lastname: Lin
authors.forename: Khoi D
authors.initials: KD
authors.lastname: Than
authors.forename: Kyuri
authors.initials: K
authors.lastname: Lee
authors.forename: Jun Beom
authors.initials: JB
authors.lastname: Park
authors.forename: Inho
authors.initials: I
authors.lastname: Jo
authors.forename: Ki Dong
authors.initials: KD
authors.lastname: Park
authors.forename: Victor C
authors.initials: VC
authors.lastname: Yang
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D050071:Bone Density Conservation Agents / Q000737:chemistry / Q000494:pharmacology*; D002021:Buffers; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D003432:Cross-Linking Reagents / Q000737:chemistry; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004339:Drug Compounding; D005780:Gelatin / Q000737:chemistry; D006735:Horseradish Peroxidase / Q000737:chemistry; D020100:Hydrogels; D006861:Hydrogen Peroxide / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D015675:Osteocalcin / Q000235:genetics / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects*; D011092:Polyethylene Glycols / Q000737:chemistry; D016133:Polymerase Chain Reaction; D019821:Simvastatin / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods; D014439:Tyramine / Q000031:analogs & derivatives / Q000737:chemistry
chemical_list: D015415:Biomarkers; D050071:Bone Density Conservation Agents; D002021:Buffers; D003432:Cross-Linking Reagents; D003692:Delayed-Action Preparations; D020100:Hydrogels; D015675:Osteocalcin; D011092:Polyethylene Glycols; D005780:Gelatin; D019821:Simvastatin; D006861:Hydrogen Peroxide; D006735:Horseradish Peroxidase; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse; D014439:Tyramine