Session II - Basic Science

Effect of OP-1 on Healing of an Infected Segmental Defect in the Rat Femur

Andrew H. Schmidt MD; Xinqian Chen MD; Louis S. Kidder PhD; William D. Lew, MS, Midwest Orthopaedic Research Foundation, Minneapolis, MN (supported by OTA Research Grant)

Hypothesis: OP-1 will induce bone formation despite an infection. Bone formation will be greater in internally stabilized, infected defects in the rat femur with OP-1 than without OP-1.

Methods: A 6-mm defect was created and stabilized with a polyacetyl plate and Kirschner wires in one femur of each of 126 adult male Sprague-Dawley rats. The rats were divided into eight groups: defect only, defect + bacteria (10⁵ CFU of Staphylococcus aureus), defect + carrier (lyophilized bovine type-I collagen, carrier for OP-1), defect + carrier + bacteria, defect + 11 mg OP-1/carrier ± bacteria, and defect + 50mg OP-1/carrier ± bacteria. The animals were euthanized at 2, 4, and 9 weeks. Quantitative radiographs were made and histological examination was performed. Templates were formed within the defect area and adjacent to the defect area. The areas of new bone formation inside the defect and outside the defect were expressed as a percentage of the defect area.

Table 1. Rate of Radiographic Bone Healing at 9 weeks

	Bone Bridging	Bone Healing
1. defect only	0/12	0/12
2. defect+infection	0/12	0/12
3. carrier	0/12	0/12
4. carrier+infection	0/12	0/12
5. 11_gOP-1/carrier	3/12 (25%)	7/12 (58%)
6. 11_gOP-1/carrier+infection	4/12 (33%)	0/12
7. 50_gOP-1/carrier	4/6 (66%)	5/6 (83%)
8. 50_gOP-1/carrier+infection	8/12 (66%)	5/12 (42%)

Results: All specimen cultures were positive in defects that received 10⁵ CFU of bacteria and negative in defects not receiving bacteria.

The 6-mm segmental defect was critical; no bone formed at 9 weeks in defects treated without OP-1. The OP-1 carrier was not osteogenic. The infection caused some osteolysis in all animals and loss of fixation at 9 weeks in some animals. The 11-mg and 50-mg doses of OP-1 induced significantly more new bone, both with and without infection, compared with defects without OP-1. Bone healing (bone connecting ends of defect, bone formation in more than 50% of defect area) and bone bridging (bone connecting ends of defect from outside the defect) were found in all OP-1 groups at 9 weeks, even with infection (Table 1). Significantly more bone formation occurred with 50mg of OP-1 than with 11mg, both with and without infection. No loss of fixation occurred at 9 weeks in infected defects with 50mg of OP-1.

Discussion: Infection in the presence of an internal fixation device is difficult to treat. Bacteria colonize the surfaces of a fixation device and form an impenetrable biofilm, rendering them resistant to the host's defenses and antibiotic therapy. Effective treatment of infection requires removal of the fixation device, which is counterproductive until the fracture has attained some degree of stability. This investigation has provided some initial evidence that OP-1 maintains its osteoinductive capability in the presence of an infected segmental defect in the rat.

Conclusions: The results of this study suggest the possibility that OP-1 may be of use clinically in the treatment of infected fractures because it maintained its osteo-inductive capability in the presence of an infected segmental defect in the rat femur.

OP-1 and carrier were generously provided by Stryker Biotech of Hopkinton, Massachusetts.