Improved spinal fusion efficacy by long-term delivery of bone morphogenetic protein-2 in a rabbit model

Abstract

Background and purpose: Various new delivery systems for recombinant human bone morphogenetic protein-2 (rhBMP-2) have been introduced to improve its efficacy in osteogenesis. Of these, we have previously developed heparin-conjugated PLGA nanospheres (HCPN) as a long-term delivery system for BMP-2. In vitro studies have shown that the BMP-2 long-term delivery system enhances the level of bone formation. However, the long-term effects of BMP-2 on spinal fusion have not been assessed. Therefore, we now tested the hypothesis that the long-term delivery of BMP-2 using HCPN improves spinal fusion compared to short-term delivery in a rabbit fusion model.

Methods: 24 adult New Zealand White rabbits underwent posterolateral fusion (6 animals in 4 groups). The autograft group received an autologous iliac chip bone graft as a positive control. The BMP-2-PN group received rhBMP-2 (20 μg per implant) and PLGA nanospheres (PN) suspended in fibrin gel, and served as a short-term release group. The HCPN group received HCPN suspended in fibrin gel without BMP-2 as a negative control. The BMP-2-HCPN group received rhBMP-2 (20 μg per implant)-bound HCPN suspended in fibrin gel and served as a long-term release group. All animals were killed 12 weeks after surgery. Manual palpation, axial tensile tests, radiography, and histological evaluations were then performed.

Results: The spinal fusion rate and Young's modulus of the fusion mass were better in the BMP-2 long-term delivery group than in the short-term delivery group at an equivalent dose. However, the outcome of the long-term delivery was inferior to that of the autograft group.

Interpretation: The HCPN system showed potential as an effective carrier that might improve the osteogenic efficacy of BMP-2 for spinal fusion.

Figure 1.

Left panel: Schematic illustration of spinal fusion via implants between the transverse processes of the fifth and lumbar vertebrae. Right panel: Scanning electron microscopic images of HCPN. Scale bar represents 500 nm.

Figure 2.

Representative radiographs showing the status of the spinal fusion between the transverse processes of the fifth and sixth lumbar vertebrae in each group.

Figure 3.

Representative stress-strain curves obtained by axial tensile testing. Longitudinal tensile stress of the 2 adjacent vertebral bodies (fifth and sixth) was measured using vice-type holders connected to a measuring device.

Figure 4.

Young's modulus determined by the result of axial tensile testing. Values represent mean (SD). ^a p < 0.05, compared to the autograft group; ^b p < 0.05, compared to the HCPN group; and ^c p < 0.05, compared to the BMP-2-PN group.