Heparin-conjugated fibrin as an injectable system for sustained delivery of bone morphogenetic protein-2.
Long-term release of bone morphogenetic protein-2 (BMP-2) can promote bone regeneration. We developed an injectable system for long-term delivery of BMP-2 by covalently conjugating heparin to fibrinogen. The heparin-conjugated fibrinogen formed an injectable, heparin-conjugated fibrin (HCF) gel when mixed with thrombin. HCF released 89.4 +/- 3.8% of the loaded BMP-2 for 13 days, whereas normal fibrin released 83.7 +/- 7.6% for the initial 3 days. BMP-2 released from HCF significantly increased alkaline phosphatase activity of cultured osteoblasts, whereas BMP-2 released from normal fibrin did not do so, indicating that BMP-2 released from HCF is bioactive and suggesting that long-term delivery of BMP-2 is advantageous over short-term delivery for bone regeneration. HCF, BMP-2-loaded HCF, and BMP-2-loaded normal fibrin containing free heparin were contained in polyester cylindrical tubes and implanted into the hind limb muscle pockets of rats for 8 weeks. Soft X-ray radiography, computed tomography, histomorphometry, calcium assay, and western blot analysis showed that BMP-2-loaded HCF yielded the most extensive bone formation among the groups. Since HCF can deliver BMP-2 over a long term, is an injectable system, and is made of clinically benign materials, this system would have advantages for clinical applications to regenerate bone.
Yang
Hee Seok
HS
Department of Bioengineering, Hanyang University , Seoul, Republic of Korea.
La
Wan-Geun
WG
Bhang
Suk Ho
SH
Jeon
Jeong-Yi
JY
Lee
Jong Ho
JH
Kim
Byung-Soo
BS
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001672:Biocompatible Materials / Q000737:chemistry; D055396:Bone Morphogenetic Protein 2 / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001861:Bone Regeneration / Q000187:drug effects; D016503:Drug Delivery Systems; D004343:Drug Implants; D005260:Female; D005337:Fibrin / Q000737:chemistry; D005782:Gels; D006493:Heparin / Q000737:chemistry; D007267:Injections; D008422:Materials Testing; D010006:Osteoblasts / Q000187:drug effects / Q000201:enzymology; D010012:Osteogenesis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D023822:Tissue Engineering
D001672:Biocompatible Materials; D055396:Bone Morphogenetic Protein 2; D004343:Drug Implants; D005782:Gels; D005337:Fibrin; D006493:Heparin; D000469:Alkaline Phosphatase