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

Yoon Shin Park; Allan E. David; Kyung Min Park; Chia Ying Lin; Khoi D. Than; Kyuri Lee; Jun Beom Park; Inho Jo; Ki Dong Park; Victor C. Yang

doi:10.1208/s12248-012-9442-6

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

Yoon Shin Park, Allan E. David, Kyung Min Park, Chia Ying Lin, Khoi D. Than, Kyuri Lee, Jun Beom Park, Inho Jo, Ki Dong Park, Victor C. Yang

Department of Molecular Medicine

Research output: Contribution to journal › Article › peer-review

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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 ₂O₂. 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.

Original language	English
Pages (from-to)	367-376
Number of pages	10
Journal	AAPS Journal
Volume	15
Issue number	2
DOIs	https://doi.org/10.1208/s12248-012-9442-6
State	Published - Apr 2013

Bibliographical note

Funding Information:
The authors gratefully acknowledge funding support provided by the National Institutes of Health. The project described was supported by Grant Number R01 AR056649 from NIAMS/NIH. This work was also supported in part by NIH R01 Grant CA114612 and partially sponsored by Grant R31-2008-000-10103-01 from the World Class University project of the MEST and NRF of South Korea. Victor C. Yang is currently a Participating Faculty in the Department of Molecular Medicine and Biopharmaceutical Sciences, College of Medicine, and College of Pharmacy, Seoul National University, South Korea.

Keywords

MC3T3-E1
MMP-3
hydrogel
osteocalcin
osteogenesis
simvastatin

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10.1208/s12248-012-9442-6

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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 2O2. 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.",

keywords = "MC3T3-E1, MMP-3, hydrogel, osteocalcin, osteogenesis, simvastatin",

author = "Park, {Yoon Shin} and David, {Allan E.} and Park, {Kyung Min} and Lin, {Chia Ying} and Than, {Khoi D.} and Kyuri Lee and Park, {Jun Beom} and Inho Jo and Park, {Ki Dong} and Yang, {Victor C.}",

note = "Funding Information: The authors gratefully acknowledge funding support provided by the National Institutes of Health. The project described was supported by Grant Number R01 AR056649 from NIAMS/NIH. This work was also supported in part by NIH R01 Grant CA114612 and partially sponsored by Grant R31-2008-000-10103-01 from the World Class University project of the MEST and NRF of South Korea. Victor C. Yang is currently a Participating Faculty in the Department of Molecular Medicine and Biopharmaceutical Sciences, College of Medicine, and College of Pharmacy, Seoul National University, South Korea.",

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doi = "10.1208/s12248-012-9442-6",

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volume = "15",

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T1 - Controlled release of simvastatin from in situ forming hydrogel triggers bone formation in MC3T3-E1 Cells

AU - Park, Yoon Shin

AU - David, Allan E.

AU - Park, Kyung Min

AU - Lin, Chia Ying

AU - Than, Khoi D.

AU - Lee, Kyuri

AU - Park, Jun Beom

AU - Jo, Inho

AU - Park, Ki Dong

AU - Yang, Victor C.

N1 - Funding Information: The authors gratefully acknowledge funding support provided by the National Institutes of Health. The project described was supported by Grant Number R01 AR056649 from NIAMS/NIH. This work was also supported in part by NIH R01 Grant CA114612 and partially sponsored by Grant R31-2008-000-10103-01 from the World Class University project of the MEST and NRF of South Korea. Victor C. Yang is currently a Participating Faculty in the Department of Molecular Medicine and Biopharmaceutical Sciences, College of Medicine, and College of Pharmacy, Seoul National University, South Korea.

PY - 2013/4

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N2 - 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 2O2. 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.

AB - 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 2O2. 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.

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

Abstract

Bibliographical note

Keywords

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