Dissociated Recombinant Human Bone Morphogenetic Protein-2 (rhBMP-2) Retains Osteoinductive Potential: An In Vivo Proxy for Burst Release

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Introduction This study investigates whether recombinant human bone morphogenetic protein-2 (rhBMP-2), once dissociated from its carrier (absorbable collagen sponge (ACS)) and transported as a soluble factor, retains sufficient osteoinductive capacity to induce ectopic bone formation. Methods ACSs were loaded with rhBMP-2 (1.5 mg/mL) and centrifuged at 500 rcf to generate supernatant run-off (SRO) containing dissociated rhBMP-2. The concentration of rhBMP-2 in the SRO was quantified by UV spectrophotometry (n = 9). In a paired design, 10 athymic nude rats received intermuscular implantation of the centrifuged ACS in the right hindlimb and injection of the corresponding SRO into the contralateral left hindlimb. At 28 days, implant sites were evaluated by micro-CT for bone volume (BV), tissue volume (TV), bone volume fraction (BV/TV), and bone mineral density (BMD), followed by histological assessment. Results In vitro quantification determined that centrifugation released an average of 11.3% ± 6% of the rhBMP-2 load into the SRO. In vivo micro-CT analysis at 28 days demonstrated mineralised tissue formation at both sites. The SRO group exhibited significantly lower total tissue volume than the ACS group (8.05 mm³ vs 29.4 mm³, P < 0.05). No statistically significant differences in bone volume fraction (BV/TV) or bone mineral density (BMD) were detected between groups. Histological evaluation confirmed that mineralised tissue variably represented bone, with the SRO group showing a spectrum from mineralised cartilage to woven bone to corticocancellous-like architecture. The ACS group demonstrated more consistent bone formation but with greater heterogeneity in maturation, including cystic and adipose-dominant phenotypes in some animals. No correlation was observed between the volume of SRO administered and the resulting mineralised tissue volume. Conclusions rhBMP-2 that dissociates from its delivery scaffold retains osteoinductive potential and can induce mineralised tissue when transported as a soluble factor. Histologically, this mineralisation ranged from mineralised cartilage to mature bone. Since clinical burst release substantially exceeds the 11% tested here, these findings represent a conservative estimate of the clinical risk. Liberated rhBMP-2, even in small quantities, may contribute to off-target mineralisation, which could be clinically relevant if formed adjacent to neural elements. These findings emphasise the need for improved controlled-release delivery strategies.

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