Enhancement of spinal fusion through BMP2 and L51P in an in vivo rat model

Oswald, Katharina Anna Christine; Bigdon, Sebastian; Gantenbein, Benjamin; Croft, Andreas Shaun; Guerrero, Julien Paul; Albers, Christoph (2021). Enhancement of spinal fusion through BMP2 and L51P in an in vivo rat model (Unpublished). In: 29th annual meeting of the European Orthopaedic Research Society. Rome. 14-18 September.

Introduction and Objective. Non-union or pseudoarthrosis remain a major unresolved complication after spinal fusion surgery, resulting in unsatisfying patient outcome and high socio-economic costs. Therefore, several biomaterials and osteobiologics have been used to improve spinal fusion, including bone morphogenetic proteins (BMP), such as BMP2. However, the necessary high dose application often lead to significant adverse effects. Furthermore, pseudoarthrosis has been reported to occur in up to 27% of all cases despite BMP2 application. The engineered BMP2 analog L51P could be a possible solution for reducing BMP doses and efficacy in clinics or could even become a possible replacement of BMP2. This pilot study aimed to demonstrate the effect of BMP2 and L51P in the enhancement of spinal fusion in rat spinal fusion model and to establish a spinal fusion rat model.
Materials and Methods. Twenty-six WISTAR rats (61.5% male, 419.04 ± 54.84 g) underwent a two-step spinal fusion surgery under full anesthesia. Firstly, a specialized designed external ring fixator (PEEK) was applied and secured with four Kirschner wires in the proximal part of the rat’s tail (cauda 4-5). Secondly, a discectomy and replacement with a β-TCP (tri-calcium-phosphate) carrier, coated with the bone morphogenetic proteins BMP2 and L51P, was conducted. Rats were assigned double-blinded into four groups according to the coating of the carrier, which was β-tri calcium phosphate (β-TCP) for all rats: (A: β-TCP with phosphate-buffered-saline (control); B: β-TCP + 1µg BMP2; C: β-TCP + 10µg BMP2; D: β-TCP + 10µg L51P). Read-outs were conducted at three and six weeks postoperatively with digital x-rays, and at 12 weeks after euthanasia with additional µCT and histology.
Results. 18 rats (A: n=5, B: n=4, C: n=4, D: n=5) had complete follow-up read-outs. Eight rats were lost in the postoperative course due to complications, such as wound dehiscence, tail necrosis or wound infection. All rats in Group C showed complete fusion in µCT data at 12 weeks postoperatively with bridging callus formation, bone in-growth and >50% carrier resorption. Rats of Group B and D exhibited signs of partial fusion, with one-sided docking of bridging callus, bone on-growth and <50% carrier resorption. Within the control Group A, no fusion nor new bone formation nor carrier resorption has occurred after 12 weeks. Bridwell-criteria analysis of conventional x-rays showed significant differences between intervention and the control group (p<0.05) at 12 weeks postoperatively.
Conclusions. In this pilot study, a spinal fusion rat model could be successfully established. With high doses of BMP2, a complete fusion was achieved in all cases. Low doses of BMP-2 and high doses of L51P resulted in partial fusion. Without growth factor stimulation, no fusion signs could be seen radiographically. Whether and to what extent a combination of low dose BMP2 and L51P can further enhance spinal fusion is subject of further investigations.

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