Local Exposure to Recombinant Human Bone Morphogenetic Protein-2 in Spinal Fusion: Limitations of Total Mass and a Proposed Anatomic Treatment Unit Dose Concentration

Recombinant human bone morphogenetic protein-2 (rhBMP-2) is effective for promoting spinal fusion, but local safety is commonly interpreted from total mass in milligrams. This structured narrative review examines the limitations of total mass and a proposed graft-normalized concentration measure that relates rhBMP-2 mass to the complete graft construct within one anatomic treatment unit (ATU). PubMed was searched on June 27, 2026, for records published from June 1, 2016 through June 26, 2026, using ((((rhBMP-2) OR (recombinant human bone morphogenetic protein-2)) AND (spine)) NOT (Maxillofacial)) NOT (Dental). The search returned 253 records. The evidence base was supplemented by backward citation searching and targeted foundational, mechanistic, anatomical, graft-volume, and regulatory sources, together with one post-search source. In interbody fusion, one ATU is one treated motion segment after cage placement. The product loading concentration, such as 1.5 mg/mL for Infuse Bone Graft (Medtronic; Memphis, Tennessee, USA), describes rhBMP-2 on its carrier before implantation. ATU dose concentration is the rhBMP-2 mass per ATU divided by the total graft volume implanted in that ATU. It is a construct-average descriptor, not a measured tissue concentration; realized exposure also depends on retention, release, mixing, spatial distribution, placement, containment, and local tissue anatomy. Across the reviewed evidence, total mass alone did not provide a sufficient general description of local biological and spatial outcomes when graft configuration, delivery, or anatomy changed. Higher nominal-dose comparisons usually changed other exposure variables, whereas equal-mass experiments produced different biological or spatial outcomes when concentration or delivery changed. These findings support reporting the completed graft construct and local anatomical context alongside mass, but they do not establish total graft volume as the biologically correct denominator or validate ATU dose concentration as an independent predictor of clinical adverse events. ATU dose concentration is therefore presented as a proposed complementary exposure descriptor requiring direct patient-level validation.