Spatiotemporal delivery of bone morphogenetic protein enhances functional repair of segmental bone defects

Abstract

Osteogenic growth factors that promote endogenous repair mechanisms hold considerable potential for repairing challenging bone defects. The local delivery of one such growth factor, bone morphogenetic protein (BMP), has been successfully translated to clinical practice for spinal fusion and bone fractures. However, improvements are needed in the spatial and temporal control of BMP delivery to avoid the currently used supraphysiologic doses and the concomitant adverse effects. We have recently introduced a hybrid protein delivery system comprised of two parts: a perforated nanofibrous mesh that spatially confines the defect region and a functionalized alginate hydrogel that provides temporal growth factor release kinetics. Using this unique spatiotemporal delivery system, we previously demonstrated BMP-mediated functional restoration of challenging 8 mm femoral defects in a rat model. In this study, we compared the efficacy of the hybrid system in repairing segmental bone defects to that of the current clinical standard, collagen sponge, at the same dose of recombinant human BMP-2. In addition, we investigated the specific role of the nanofibrous mesh tube on bone regeneration. Our results indicate that the hybrid delivery system significantly increased bone regeneration and improved biomechanical function compared to collagen sponge delivery. Furthermore, we observed that presence of the nanofiber mesh tube was essential to promote maximal mineralized matrix synthesis, prevent extra-anatomical mineralization, and guide an integrated pattern of bone formation. Together, these results suggest that spatiotemporal strategies for osteogenic protein delivery may enhance clinical outcomes by improving localized protein retention.

Hydrogel-based Delivery of rhBMP-2 Improves Healing of Large Bone Defects Compared With Autograft

“…It is thought that research that demonstrates efficacy with use of lower doses and/or a more sustained delivery of rhBMP-2 could thus lead to increased use of rhBMP-2 in place of autografts. We have previously demonstrated improved functional bone regeneration when directly comparing the NMA-rhBMP-2 hybrid delivery system with the ACS-rhBMP-2 delivery system for the same dose of rhBMP-2 [8,27]. However, the efficacy of the NMA-rhBMP-2 hybrid delivery system has never been compared with use of live autograft to augment healing of critically sized long bone segmental defects.…”

“…All materials were aseptically prepared in a laminar flow hood, and the hydrogels were stored sterile overnight at 4°C. During surgery, 150 lL of alginate hydrogel, kept on ice between uses, was injected into the defect space through the perforations in the NFM tube as previously established [8,27,34].…”

“…The central 121 image slices corresponding to approximately the central 4.6 mm of the defect length were analyzed for differences. BV and BD across the two treatment groups and time points were calculated for statistical comparisons (n = 14 per group) as described previously [8,27,34]. To accurately quantify the amount of new bone formation in the presence of mature autograft material, the respective 2-week BVs were used as a baseline to subtract from the subsequent volumes for each sample.…”

“…Torsional tests to failure were performed on samples harvested at 12 weeks postsurgery (n = 9 per treatment group) as established earlier [8,27,28,34]. Frozen samples were thawed at room temperature, dissected to remove all soft tissues surrounding the defects, and then the fixation plates were removed.…”

“…We have previously observed higher mineral content and biomechanical properties in critically sized femoral segmental defects treated with a perforated nanofiber mesh enclosing RGD-alginate and rhBMP-2 (NMA-rhBMP-2) hybrid delivery system at equivalent doses and with advantageous rhBMP-2 release kinetics as compared with ACS-rhBMP-2 [8,9,27,28]. However, its performance relative to autograft, the gold standard, is unknown.…”