Early-term and mid-term histologic events during single-level posterolateral intertransverse process fusion with rhBMP-2/collagen carrier and a ceramic bulking agent in a nonhuman primate model: implications for bone graft preparation.
METHODS
We used a nonhuman primate lumbar intertransverse process arthrodesis model to evaluate biological cascade of bone formation using different carrier preparation methods with a single dose of recombinant human bone morphogenetic protein-2 (rhBMP-2) at early time points.


OBJECTIVE
To examine early-term/mid-term descriptive histologic and computerized tomographic events in single-level uninstrumented posterolateral nonhuman primate spinal fusions using rhBMP-2/absorbable collagen sponge (ACS) combined with ceramic bulking agents in 3 different configurations.


BACKGROUND
rhBMP-2 on an ACS carrier alone leads to consistent posterolateral lumbar spine fusions in lower-order animals; however, these results have been difficult to replicate in nonhuman primates.


METHODS
Twelve skeletally mature, rhesus macaque monkeys underwent single-level posterolateral arthrodesis at L4-L5. A hydroxyapatite/β-tricalcium phosphate ceramic bulking agent in 3 formulations was used in the treatment groups (n=3). When used, rhBMP-2/ACS at 1.5 mg/cm (3.0 mg rhBMP-2) was combined with 2.5 cm of ceramic bulking agent per side. Animals were euthanized at 4 and 12 weeks postoperative. Computerized tomography scans were performed immediately postoperatively and every 4 weeks until they were euthanized. Sagittal histologic sections were evaluated for bone histogenesis and location, cellular infiltration of the graft/substitute, and bone remodeling activity.


RESULTS
Significant histologic differences in the developing fusion appeared between the 3 rhBMP-2/ACS treatment groups at 4 and 12 weeks. At 4 weeks, bone formation appeared to originate at the transverse process and the intertransverse membrane. Cellular infiltration was greatest in granular ceramic groups compared with matrix ceramic group. Minimal to no residual ACS was identified at the early time point. At 12 weeks, marked ceramic remodeling was observed with continued bone formation noted in all carrier groups.


CONCLUSIONS
At the early time period, histology showed that bone formation appeared to originate at the transverse processes and the intertransverse membrane, indicating that the dorsal muscle bed may not be the only location for bone formation. Histology also showed that the collagen carrier for rhBMP-2 is mostly resorbed by 4 weeks. Our results and previous literature indicate that ceramic bulking agents are needed to provide resistance to compression caused by paraspinal muscles on the fusion bed in the posterolateral environment. Histology showed that ceramic bulking agents may offer long-term scaffolding and a structure to supporting bone formation of the developing fusion mass.
*Department of Orthopaedic Surgery, Division of Spine Surgery, The Ohio State University, Columbus, OH †Department of Orthopaedic Surgery, Spine Service, University of California, Davis, CA ‡Department of Orthopaedic Surgery, Medical College of Wisconsin §Colleges of Dentistry and Engineering, Marquette University, Milwaukee, WI ∥Department of Orthopaedic Surgery, University of Louisville, Louisville, KY.
Safdar N
SN
Khan
Jeffrey M
JM
Toth
Kavita
K
Gupta
Steven D
SD
Glassman
Munish C
MC
Gupta
D000818:Animals; D001672:Biocompatible Materials / Q000494:pharmacology; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology*; D016025:Bone Transplantation; D002516:Ceramics / Q000494:pharmacology*; D003094:Collagen / Q000737:chemistry*; D006801:Humans; D008159:Lumbar Vertebrae / Q000033:anatomy & histology / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000601:surgery*; D008253:Macaca mulatta / Q000502:physiology*; D023421:Models, Animal; D010012:Osteogenesis / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D013123:Spinal Fusion / Q000379:methods*; D014057:Tomography, X-Ray Computed; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D001672:Biocompatible Materials; D055396:Bone Morphogenetic Protein 2; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C499469:recombinant human bone morphogenetic protein-2; D003094:Collagen