Is Heparin Effective for the Controlled Delivery of High-Dose Bone Morphogenetic Protein-2?
Sustained release of bone morphogenetic protein (BMP)-2 by heparin-contained biomaterials is advantageous for bone tissue regeneration using low-dose BMP-2. However, its effect with high-dose BMP-2 is still unclear and should be clarified considering the clinical use of a high dose of BMP-2 in spine and oral surgery. This study aimed to evaluate the efficacy of a heparin-conjugated collagen sponge (HCS) with high-dose BMP-2 delivery by investigating in vivo initial osteogenic regulation and bone healing over 12 weeks in comparison with that of an absorbable collagen sponge (ACS). The in vitro BMP-2 release profile in the HCS exhibited a lower burst followed by a sustained release of BMP-2, whereas that of the ACS showed an initial burst phase only. As a result of a lower burst, the HCS-BMP group showed higher expression of bone-forming/resorbing markers and enhanced activation of osteoclasts than the ACS-BMP group within the scaffold of defect after 7 days, which is presumed to be because of retention of relatively higher amounts of BMP-2. However, the surrounding calvariae were less resorbed in the HCS-BMP group, compared with the aggressive resorptive response in the ACS-BMP group. Microcomputed tomography and histology revealed that HCS-BMP guided more effective bone regeneration of central defect over time inducing minor ossification at the defect exterior, whereas ACS-BMP exhibited excessive ossification at the defect exterior. These results showed that HCS-mediated BMP-2 delivery at a high dose has advantages over ACS, including less early resorption of surrounding bone tissue and higher efficacy in compact bone regeneration over a longer period, highlighting a clinical feasibility of this technology.
1 BK21 2nd Program for Craniomaxillofacial Life Science, Department of Maxillofacial Cell and Developmental Biology, School of Dentistry, Seoul National University , Seoul, Republic of Korea.
Ri Youn
RY
Kim
2 Dental Research Institute, Seoul National University , Seoul, Republic of Korea.
Beomseok
B
Lee
3 Regenerative Medicine Research Center, Dalim Tissen Co., Ltd. , Seoul, Republic of Korea.
Si-Nae
SN
Park
3 Regenerative Medicine Research Center, Dalim Tissen Co., Ltd. , Seoul, Republic of Korea.
Jae-Hyung
JH
Ko
2 Dental Research Institute, Seoul National University , Seoul, Republic of Korea.
In Sook
IS
Kim
1 BK21 2nd Program for Craniomaxillofacial Life Science, Department of Maxillofacial Cell and Developmental Biology, School of Dentistry, Seoul National University , Seoul, Republic of Korea.|2 Dental Research Institute, Seoul National University , Seoul, Republic of Korea.|4 Department of Oral and Maxillofacial Surgery, School of Dentistry, Seoul National University , Seoul, Republic of Korea.
Soon Jung
SJ
Hwang
D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001862:Bone Resorption / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003094:Collagen / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D003692:Delayed-Action Preparations / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006493:Heparin / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley
C525720:Bmp2 protein, rat; D055396:Bone Morphogenetic Protein 2; D003692:Delayed-Action Preparations; D006493:Heparin; D003094:Collagen