Craniomaxillofacial Bone Regeneration with Attenuated Early Inflammatory Response by Sustained-release of BMP-2 from a Supramolecular Polymer Slurry

Abstract Purpose Bone morphogenic proteins (BMPs) are pivotal in craniomaxillofacial surgery for bone reconstruction. However, their side effects, such as severe edema and local inflammation, limit their use. Nanoscale peptide amphiphiles (PAs) self-assemble into nanofibers and can act as sustained-release carriers for biological molecules, supporting tissue regeneration. This study investigates the impact of PA gels on in vitro osteogenic differentiation and bone repair and inflammation in craniomaxillofacial bone defect models in vivo. Methods BMP-2 release from PA gels was analyzed. Human bone marrow stromal cells (BMSCs) were treated with growth medium or medium containing BMP-2 and PAs. Osteogenic differentiation was assessed using quantitative RT-PCR for osteogenesis-specific genes. Bone defects were created in rabbit calvaria and rat maxilla and treated with collagen material containing BMP-2 with or without PA gels. Control groups included collagen material only. Bone tissue and surrounding soft tissue were harvested for radiographic and histologic analyses and inflammation-related gene expression. Immunohistochemical (IHC) staining was performed for inflammatory responses. Results BMP-2 was released from PA gels in a sustained manner, significantly increasing osteogenic activity in BMSCs compared to controls. In bone defect models, collagen with low-dose BMP-2 incorporating PA gels showed robust bone regeneration, comparable to high-dose BMP-2 without PAs. Inflammatory markers, such as IL6, TNF-α, and Cox2, were elevated in high-dose BMP-2 groups but normalized in groups treated with BMP-2 incorporating PAs, consistent with IHC findings. Conclusions PAs with low-dose BMP-2 may be a viable alternative to high-dose BMP-2 in craniofacial surgery, offering reduced inflammation and effective bone regeneration. Lay Summary This study evaluates the potential of a hybrid material combining peptide amphiphile (PA) nanostructures and collagen particles as an alternative for bone reconstruction in craniomaxillofacial surgery. While bone morphogenetic proteins (BMPs) are effective for bone regeneration, their use is often limited by side effects like inflammation. PA gels mimic extracellular structures, enabling sustained BMP-2 release and promoting tissue regeneration. The study demonstrated that low-dose BMP-2 combined with PA gels supports robust bone regeneration while reducing inflammation, as compared to high-dose BMP-2, which elevated inflammation-related gene expression. These findings suggest that PA gels with low-dose BMP-2 offer a promising, less inflammatory alternative for bone reconstruction in craniomaxillofacial surgery.