title: Heparin-conjugated fibrin as an injectable system for sustained delivery of bone morphogenetic protein-2.
abstract: 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.
authors.affiliation: Department of Bioengineering, Hanyang University , Seoul, Republic of Korea.
authors.forename: Hee Seok
authors.initials: HS
authors.lastname: Yang
authors.forename: Wan-Geun
authors.initials: WG
authors.lastname: La
authors.forename: Suk Ho
authors.initials: SH
authors.lastname: Bhang
authors.forename: Jeong-Yi
authors.initials: JY
authors.lastname: Jeon
authors.forename: Jong Ho
authors.initials: JH
authors.lastname: Lee
authors.forename: Byung-Soo
authors.initials: BS
authors.lastname: Kim
mesh_terms: 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
chemical_list: D001672:Biocompatible Materials; D055396:Bone Morphogenetic Protein 2; D004343:Drug Implants; D005782:Gels; D005337:Fibrin; D006493:Heparin; D000469:Alkaline Phosphatase