Controlled release of simvastatin from in situ forming hydrogel triggers bone formation in MC3T3-E1 cells

AAPS J. 2013 Apr;15(2):367-76. doi: 10.1208/s12248-012-9442-6. Epub 2012 Dec 19.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Blotting, Western
  • Bone Density Conservation Agents / chemistry
  • Bone Density Conservation Agents / pharmacology*
  • Buffers
  • Cell Differentiation / drug effects
  • Cell Line
  • Cell Proliferation / drug effects
  • Chemistry, Pharmaceutical
  • Cross-Linking Reagents / chemistry
  • Delayed-Action Preparations
  • Dose-Response Relationship, Drug
  • Drug Compounding
  • Gelatin / chemistry
  • Horseradish Peroxidase / chemistry
  • Hydrogels
  • Hydrogen Peroxide / chemistry
  • Hydrogen-Ion Concentration
  • Kinetics
  • Matrix Metalloproteinase 13 / genetics
  • Matrix Metalloproteinase 13 / metabolism
  • Mice
  • Osteoblasts / drug effects*
  • Osteoblasts / metabolism
  • Osteocalcin / genetics
  • Osteocalcin / metabolism
  • Osteogenesis / drug effects*
  • Polyethylene Glycols / chemistry
  • Polymerase Chain Reaction
  • Simvastatin / chemistry
  • Simvastatin / pharmacology*
  • Solubility
  • Technology, Pharmaceutical / methods
  • Tyramine / analogs & derivatives
  • Tyramine / chemistry


  • Biomarkers
  • Bone Density Conservation Agents
  • Buffers
  • Cross-Linking Reagents
  • Delayed-Action Preparations
  • Hydrogels
  • Osteocalcin
  • Polyethylene Glycols
  • Gelatin
  • Simvastatin
  • Hydrogen Peroxide
  • Horseradish Peroxidase
  • Matrix Metalloproteinase 13
  • Mmp13 protein, mouse
  • Tyramine