Inflammatory characteristics of rhBMP-2 in vitro and in an in vivo rodent model.
METHODS
In vivo and in vitro model.


OBJECTIVE
Investigate soft-tissue inflammation caused by rhBMP-2.


BACKGROUND
Although rhBMP-2 produces excellent rates of fusion in the spine, dysphagia and respiratory compromise have occurred when used in the neck. The mechanism of the swelling and inflammatory response has yet to be fully elucidated.


METHODS
ELISA kits (IL-6, IL-10, TNF-α) were used to measure cytokine levels at different concentrations of rhBMP-2. Absorbable collagen sponges were implanted with or without different concentrations of rhBMP-2 into the backs of rats subcutaneously (SC) and intramuscularly (IM). Magnetic resonance imaging was used to measure inflammation at 3 hours and 2, 4, and 7 days. The inflammatory volumes were measured and compared using MIPAV software. Rats were killed after 7 days and studied.


RESULTS
IL-6, IL-10, and TNF-α release was dose-dependent. Soft-tissue edema after rhBMP-2 implantation was also dose-dependent, peaking at 3 hours SC, after SC and IM implantations, and on day 2 IM after IM implantation. All formed a granuloma-type mass after SC insertion. The mass was much larger in the 10 and 20 μg/10 μL (high-concentration) groups. The inflammatory response did not diffuse across physiologic barriers (subcutaneous fascia). Both high-dose groups were associated with encapsulated hematomas and a significant increase in the inflammatory zone.


CONCLUSIONS
Swelling and inflammation after rhBMP-2 use are dose-dependent. Swelling may be due to direct contact as well as spread in the plane of access. The causes are a robust inflammatory reaction as well as sterile seroma and encapsulated hematoma formation.
Department of Orthopaedic Surgery, University of California, Los Angeles, CA 90404, USA
Kwang-Bok
KB
Lee
Cyrus E
CE
Taghavi
Kyung-Jin
KJ
Song
Chananit
C
Sintuu
Jeong Hyun
JH
Yoo
Gun
G
Keorochana
Shia-Tzu
ST
Tzeng
Zhiqiang
Z
Fei
Jen-Chung
JC
Liao
Jeffrey C
JC
Wang
D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000008:administration & dosage / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006406:Hematoma / Q000139:chemically induced* / Q000473:pathology*; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D009333:Neck / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000633:toxicity; D012377:Rodentia; D049291:Seroma / Q000139:chemically induced* / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000008:administration & dosage / Q000633:toxicity*
D055396:Bone Morphogenetic Protein 2; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C499469:recombinant human bone morphogenetic protein-2