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Local sustained delivery of bioactive molecules from biomaterials is a promising strategy to enhance bone regeneration. To optimize delivery vehicles for bone formation, the design characteristics are tailored with consequential effect on bone morphogenetic protein-2 (BMP-2) release and bone regeneration. Complying with the 3R principles (Replacement, Reduction, and Refinement), the growth factor release is often investigated in vitro using several buffers to mimic the in vivo physiological environment. However, this remains an unmet need. Therefore, this study investigates the in vitro-in vivo correlation (IVIVC) of BMP-2 release from complex delivery vehicles in several commonly used in vitro buffers: cell culture model, phosphate buffered saline, and a strong desorption buffer. The results from this study showed that the release environment affected the BMP-2 release profiles, creating distinct relationships between release versus time and differences in extent of release. According to the guidance set by the U.S. Food and Drug Administration (FDA), IVIVC resulted in level A internal predictability for individual composites. Since the IVIVC was influenced by the BMP-2 loading method and composite surface chemistry, the external predictive value of the IVIVCs was limited. These results show that the IVIVCs can be used for predicting the release of an individual composite. However, the models cannot be used for predicting in vivo release for different composite formulations since they lack external predictability. Potential confounding effects of drug type, delivery vehicle formulations, and application site should be added to the equation to develop one single IVIVC applicable for complex delivery vehicles. Altogether, these results imply that more sophisticated in vitro systems should be used in bone regeneration to accurately discriminate and predict in vivo BMP-2 release from different complex delivery vehicles.

Off-the-shelf availability in large quantities, drug delivery functionality, and modifiable chemistry and mechanical properties make synthetic polymers highly suitable candidates for bone grafting. However, most synthetic polymers lack the ability to support cell attachment, proliferation, migration, and differentiation, and ultimately tissue formation. Incorporating anionic peptides into the polymer that mimics acidic proteins, which contribute to biomineralization and cellular attachment, could enhance bone formation. Therefore, this study investigates the effect of a phosphate functional group on osteoconductivity and BMP-2-induced bone formation in an injectable and biodegradable oligo[(polyethylene glycol) fumarate] (OPF) hydrogel. Three types of OPF hydrogels were fabricated using 0%, 20%, or 40% Bis(2-(methacryloyloxy)ethyl) phosphate creating unmodified OPF-noBP and phosphate-modified OPF-BP20 and OPF-BP40, respectively. To account for the osteoinductive effect of various BMP-2 release profiles, two different release profiles (i.e., different ratios of burst and sustained release) were obtained by varying the BMP-2 loading method. To investigate the osteoconductive effect of phosphate modification, unloaded OPF composites were assessed for bone formation in a bone defect model after 3, 6, and 9 weeks. To determine the effect of the hydrogel phosphate modification on BMP-2-induced bone formation, BMP-2 loaded OPF composites with differential BMP-2 release were analyzed after 9 weeks of subcutaneous implantation in rats. The phosphate-modified OPF hydrogels (OPF-BP20 and OPF-BP40) generated significantly more bone in an orthotopic defect compared to the unmodified hydrogel (OPF-noBP). Furthermore, the phosphate functionalized surface-enhanced BMP-2-induced ectopic bone formation regardless of the BMP-2 release profile. In conclusion, this study clearly shows that phosphate functional groups improve the osteoconductive properties of OPF and enhanced BMP-2-induced bone formation. Therefore, functionalizing hydrogels with phosphate groups by crosslinking monomers into the hydrogel matrix could provide a valuable method for improving polymer characteristics and holds great promise for bone tissue engineering.