Local and systemic immune responses during rhBMP-2 mediated bone regeneration are dose-dependent in rat model of critical-sized bone defect healing.

Abstract

Bone morphogenetic proteins (BMPs) are among the most potent clinical therapeutics for promoting bone regeneration, yet their use is limited by potential adverse events such as heterotopic bone formation, osteolysis, and soft tissue inflammation. Sustained release delivery systems may reduce the minimum effective BMP dose needed to induce functional bone healing but have yet to be fully characterized or translated to clinical use. Here, we utilized a rat model of segmental femur defect healing to investigate the dose-dependent inflammatory effects of BMP delivery in a hydrogel-based system by profiling local and systemic immune responses. Defects were treated with the delivery vehicle only (control), a minimum effective dose of BMP-2, or a high dose of BMP-2. The minimum effective BMP-2 dose induced comparable bone formation within the defects but significantly less ossification outside the defect region relative to the high dose. Immune profiling revealed significant dose-dependent effects of BMP-2 delivery on cellular and proteomic signatures both locally and systemically. Notably, however, no significant differences in immune response markers were detected between the vehicle only control and minimum effective dose groups at any timepoint. This study confirms that BMP-2 delivered at high doses incites strong inflammatory responses locally and systemically, but sustained delivery of a minimum effective dose can regenerate bone without provoking bone formation outside the intended delivery location or inflammatory side effects. The results of this study are limited to only two BMP-2 doses and a sustained-release delivery system, and may not remain true in the FDA-approved collagen sponge.