Abstract
Autologous bone grafting stands as the prevailing solution for addressing critical defects, despite its associated drawbacks such as prolonged operation times and safety concerns. In contrast, while convenient, commercially available off-the-shelf bone substitutes often fall short of achieving the efficacy of autografts. Recognizing this gap, this thesis explores a novel
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approach: replacing killed bacteria with synthetic bacterial cell wall components, known as pathogen recognition receptor (PRR) ligands, to enhance the performance of bone substitutes.
To elucidate the potential of PRR ligands, comprehensive in vitro studies were undertaken. These studies investigated the effects of PRR ligands on human-derived mesenchymal stromal cells and monocytes, shedding light on their ability to modulate the immune response and potentially stimulate osteogenesis. Notably, nucleic acid-based PRR ligands, including CpG ODN C and Poly(I:C), emerged as promising candidates for their capacity to promote osteogenesis through immunomodulation.
Transitioning from in vitro to in vivo experimentation, an investigation was conducted using ovariectomized rats with closed femur fractures. Local injection of PRR ligands at the fracture site was expected to facilitate early inflammation resolution and accelerate fracture healing. However, contrary to expectations, the results of this study failed to demonstrate significant effects on either early inflammation or fracture healing outcomes. Despite this setback, further research efforts were directed towards mimicking the response of killed bacteria through the combination of PRR ligands. Although these attempts yielded promising results, they only partially replicated the beneficial effects observed with killed S. aureus.
In conclusion, the exploration of proinflammatory agents as enhancers of bone formation represents a high-risk, high-reward endeavor. While the potential benefits are substantial, the risks that come with caution and thorough evaluation are also important. Moreover, the complexities of the immune system's response to bone injuries underscore the importance of advancing in vitro and in vivo models to screen and validate osteo-immunomodulatory strategies effectively.
Future research endeavors should prioritize the development of sophisticated experimental models capable of faithfully replicating the intricate interplay between immune responses and bone regeneration. By harnessing the potential of PRR ligands and other innovative approaches, the field stands poised to revolutionize the treatment landscape for bone defects and fractures, offering renewed hope for patients grappling with these challenging conditions.
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