Article
Increased Lumbar Fusion by a Novel Pro-osteogenic Small Molecule – Preclinical Evaluation in a Rat Model
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Authors
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Lisa Findeisen
- OUPC, Uniklinikum Dresden, TFO, Uniklinikum Dresden, Dresden, Germany
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Corina Vater
- OUPC, Uniklinikum Dresden, TFO, Uniklinikum Dresden, Dresden, Germany
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Julia Bolte
- OUPC, Uniklinikum Dresden, TFO, Uniklinikum Dresden, Dresden, Germany
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Luisa Straßburger
- OUPC, Uniklinikum Dresden, TFO, Uniklinikum Dresden, Dresden, Germany
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Lucas-Maximilian Matuszewski
- OUPC, Uniklinikum Dresden, TFO, Uniklinikum Dresden, Dresden, Germany
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Deepak Bushan Raina
- Lund Universit, Faculty of Medicine, Department of Clinical Sciences Lund, Orthopedics, Lund, Sweden
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Alexander C. Disch
- OUPC, Uniklinikum Dresden, Dresden, Germany
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Stefan Zwingenberger
- OUPC, Uniklinikum Dresden, TFO, Uniklinikum Dresden, Dresden, Germany
| Published: | October 26, 2021 |
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Outline
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Objectives: To accelerate spinal fusion rates and reduce donor site comorbidities of autologous bone harvesting, the development of pro-osteogenic graft substitutes is aimed.
The pro-osteogenic potential of a novel potent small molecule (KMN-159) was investigated by using mineralized collagen matrix (MCM) scaffolds as carrier in a posterolateral spinal fusion rat model. KMN-159 is a novel, highly selective prostaglandin-receptor (EP4) agonist. We hypothesized that KMN-159 would lead to a dose-dependent increase of bone volume comparable to bone morphogenetic protein 2 (BMP-2).
Methods: This in vivo study was performed on 144 10-week-old male Wistar rats. According to the implant, rats were randomized into 6 groups (n = 24): 1) negative control, no scaffold (control), 2) scaffold only (MCM), 3) positive control, MCM + 20 µg BMP-2, 4) - 6) MCM + 20, 200 or 2000 µg KMN-159. All experiments approved by the Local Animal Care Committee. The scaffolds were implanted bilaterally onto the transverse processes of L4 and L5 with fixing the implant by adapting the soft tissue around it. To examine further parameters X-ray, µCT, histological and biomechanical analysis were performed on the vertebrae L4/L5 after 3 or respectively 6 weeks of observation.
1-way ANOVA and Tukey's post-hoc test was used for statistical analysis between the groups. Differences were considered significant when p < 0.05.
Results and Conclusion: All animals survived the surgeries and the observation periods. µCT evaluation showed a significant increase when the scaffolds were functionalized with 20 µg BMP- and 2000 µg of KMN-159 (Table 1 [Tab. 1]; mean ± SD, significance against control * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001 ). In line with this, radiographic and histological grading revealed a significantly higher fusion score for the KMN-159 and BMP-2 groups compared to control and MCM group (Figure 1 [Fig. 1]). Number of vessels, osteoblasts and osteoclasts differed significantly between the treatment-groups.
Biomechanical testing revealed significant differences in breaking force between control and groups 4) - 6).
With respect to bone volume and grade of fusion 2000 µg of the novel small molecule KMN-159 was as sufficient as 20 µg BMP-2 in a posterolateral spinal fusion rat model. This might constitute as a beneficial alternative to autologous bone or BMP-2 considering side effects and comorbidities.
