Artikel
A novel selective prostaglandin-receptor EP4-agonist promotes posterolateral spinal fusion in a rat model
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Autoren
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Stefan Zwingenberger
- Universitätsklinikum Carl Gustav Carus, UniversitätsCentrum für Orthopädie, Unfall- & Plastische Chirurgie, Dresden, Germany
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Xinggui Tian
- Universitätsklinikum Carl Gustav Carus, UniversitätsCentrum für Orthopädie, Unfall- & Plastische Chirurgie, Dresden, Germany
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Lisa Findeisen
- Universitätsklinikum Carl Gustav Carus, UniversitätsCentrum für Orthopädie, Unfall- & Plastische Chirurgie, Dresden, Germany
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Deepak Raina
- Lund University, Department of Clinical Sciences, Orthopedics, Lund, Sweden
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Hannes Kern
- Universitätsklinikum Carl Gustav Carus, UniversitätsCentrum für Orthopädie, Unfall- & Plastische Chirurgie, Dresden, Germany
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Julia Bolte
- Universitätsklinikum Carl Gustav Carus, UniversitätsCentrum für Orthopädie, Unfall- & Plastische Chirurgie, Dresden, Germany
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Niels Modler
- Technische Universität Dresden, Institut für Leichtbau und Kunststofftechnik, Dresden, Germany
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Anja Winkler
- Technische Universität Dresden, Institut für Leichtbau und Kunststofftechnik, Dresden, Germany
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Robert Gottwald
- Technische Universität Dresden, Institut für Leichtbau und Kunststofftechnik, Dresden, Germany
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Klaus-Dieter Schaser
- Universitätsklinikum Carl Gustav Carus, UniversitätsCentrum für Orthopädie, Unfall- & Plastische Chirurgie, Dresden, Germany
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Alexander C. Disch
- Universitätsklinikum Carl Gustav Carus, UniversitätsCentrum für Orthopädie, Unfall- & Plastische Chirurgie, Dresden, Germany
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Corina Vater
- Universitätsklinikum Carl Gustav Carus, UniversitätsCentrum für Orthopädie, Unfall- & Plastische Chirurgie, Dresden, Germany
| Veröffentlicht: | 23. Oktober 2023 |
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Gliederung
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Objectives: Posterolateral spinal fusion (PLF) is a commonly used procedure in orthopedic surgery to treat spinal instability. However, it is challenging to achieve a robust fusion due to the long bone crawl distance. The only FDA-approved osteoinductive factor, bone morphogenetic protein 2 (BMP-2), is expensive and has severe side effects. A novel EP4 selective agonist (KMN-159) was developed and our recent study found that it can act as an osteopromotive factor to stimulate the repair of critical-size femoral bone defects in rats in a dose-dependent manner. KMN-159 is inexpensive and involves facile production, resistance to heat and has a long shelf life. Based on the osteopromotive properties of this selective EP4 agonist, we hypothesized that KMN-159 could also aid in bone formation in a spinal fusion model.
Methods: This study was performed on 192, 10-week-old male Wistar rats. According to the implant, rats were randomized into 8 groups (n = 12 per group): 1) SHAM (negative control), 2) MCM (scaffold only), 3) MCM + 20 µg BMP-2 (positive control), 4-8) MCM + 0.2, 2, 20, 200 or 2,000 µg KMN-159. A posterolateral intertransverse process spinal fusion at L4 to L5 was performed bilaterally by implanting group dependent scaffolds (see above) or left empty in the SHAM group. Animals were euthanized after 3 weeks and 6 weeks for µCT and biomechanical testing analysis.
Results and conclusion: KMN-159 promoted new bone formation in a dose-dependent manner at 3 weeks and 6 weeks as verified by µCT. When functionalized with 2,000 µg KMN-159, the implant significantly promoted bone formation and achieved spinal fusion effects comparable to BMP-2. When considering the lower doses, the µCT-based bone volume was higher in the 20, 200 and 2,000 µg KMN-159 groups when compared with 0.2 and 2 µg KMN-159 groups (Figure 1A). The new bone of the lower dose groups (0.2 and 2 µg) mainly originated from the base of the transverse processes. The biomechanical testing showed that the 20, 200 and 2,000 µg KMN-159 dose groups developed strength comparable to the BMP-2 group and were all higher than SHAM, MCM and the lower doses (0.2 and 2 µg) of KMN-159 (Figure 1B).
In this study, KMN-159 promoted spinal fusion by dose-dependent bone regeneration, achieving comparable spinal fusion effects to BMP-2 at doses of 20, 200, and 2,000 µg. KMN-159, as a selective EP4 receptor agonist, has good chemical stability and pharmacological properties and does not pose risks of ectopic bone formation, even at doses as high as 2000 µg. Based on these properties, KMN-159 could become a significant osteopromotive factor for use in spinal fusion surgery.
