Background: Recombinant human osteogenic protein-1 (rhOP-1),
combined with a collagen carrier, has been shown to induce new-bone formation
in a variety of animal models. The purpose of the present investigation was to
test the hypotheses that rhOP-1 would accelerate bone formation in an
internally stabilized, chronically infected, critical-size defect in the rat
femur and that this effect would be enhanced by the administration of systemic
antibiotic.
Methods: A 6-mm segmental defect was created surgically, stabilized
with a polyacetyl plate and six Kirschner wires, and contaminated with
104 colony-forming units of Staphylococcus aureus in one
femur in each of 168 Sprague-Dawley rats. After two weeks, these infected
defects were débrided surgically and were assigned to one of six
treatment groups. The defects in the thirty animals in the first group
received lyophilized collagen carrier mixed with 200 µg of rhOP-1 dissolved
in buffer, the defects in the thirty animals in the second group received
carrier with 20 µg of rhOP-1 in buffer, and the defects in the twenty-four
control animals in the third group received carrier mixed with buffer without
rhOP-1. The last three groups were treated identically to the first three
groups, except that the animals also received the antibiotic ceftriaxone for
twenty-eight days after débridement. The animals were killed at two,
four, eight, or twelve weeks after débridement. Newly mineralized
callus within the defect, and adjacent to and bridging the outside of the
defect, was assessed with use of quantitative high-resolution radiography,
microcomputed tomography, torsional failure testing, and histological analysis
of undecalcified sections.
Results: Bacterial cultures confirmed the presence of a chronic
infection during the study period in all animals. At the later time-points,
significantly more newly mineralized callus was present within and adjacent to
the débrided defects that had been treated with 200 µg of rhOP-1,
whereas minimal amounts of callus were present within and adjacent to the
defects that had been treated without rhOP-1 and with 20 µg of rhOP-1. At
eight and twelve weeks after débridement, there was significantly more
newly mineralized callus in the group that had been treated with 200 µg of
rhOP-1 with antibiotic than in the group that had been treated with 200 µg
of rhOP-1 without antibiotic (p < 0.05). At twelve weeks, the values for
torque, energy to failure, and linear stiffness for femora that had been
treated with 200 µg of rhOP-1 with antibiotic were not significantly
different from the values for intact, contralateral control femora, whereas
the values for femora that had been treated with 200 µg of rhOP-1 without
antibiotic remained significantly lower than those for the intact,
contralateral controls (p < 0.05).
Conclusions: Recombinant human osteogenic protein-1 maintained its
osteoinductive capability in the presence of chronic infection, and this
property was enhanced by antibiotic therapy. No substantial callus formed in
the infected defects without a sufficiently high dose of rhOP-1.
Clinical Relevance: The treatment of an infection at the site of a
fracture often necessitates removal of internal fixation. However, internal
fixation is needed for fracture stability. This study presents an intervention
that may accelerate fracture-healing in the presence of infection and
colonized hardware, thereby permitting earlier removal of the hardware and
more timely and effective treatment of the infection.