AUGMENTATION OF BONE REPAIR

Participants: Patil, P., Bonadio, J., Smiley, E., Debano, C., Nolan, B., Sweet, K., Stock, M., Goldstein, S.

Keywords: gene therapy, fracture healing, animal model

Introduction

The treatment of fracture depends on anatomic location, the severity of the traumatic injury, amongst other variables. For simple closed fractures, placement of a cast will control pain and facilitate healing. However, complex fractures that heal poorly present a challenge usually required some form of fixation. Rapid new bone growth between the fragments is critical to success in part because it mitigates against fixator instability. To facilitate new bone growth many methods may be used, most commonly bone graft. However, grafts may become infected or may provide insufficient bone.

As recombinant proteins are becoming more popular in the treatment of fractures to stimulate new bone growth new concerns are raised. Relatively large dose of such proteins are needed which raises the concerns of expense and toxicity. Gene therapy may be a more efficient means of delivery for such osteoinductive molecules. We are testing the efficacy of delivery of genetic material to enhance healing of tissue defects.

Materials and Methods

Beagles were utilized for this study. These animals are chosen because of bone repair and remodeling characteristics as well as uniform genetics. These animals had bilateral/unilateral mid-diaphyseal defects (2.0, 1.6, or 1.0 cm) created by instrument guided osteotomies, followed by implantation of gene activated matrices that included varying doses of the DNA for PTH_1-34 in a collagen type I sponge. Controls included empty sponges as well as canine allografts as a positive control. Endpoints for this evaluation included biweekly radiographs, histologic analysis, and some biomechanical testing.

Using a custom drill guide, each of six pinsites are drilled using a 3.0mm drill and pinned with a 4.0mm stainless steel Schanz screws. The pins are advanced until purchase of the second cortex is observed. After pinning is complete, the external fixator is securely fastened to the pins. An incision is then made between the middle two pins on the anterio-medial aspect of the tibia. The periosteum is elevated around both tibia and fibula, and a section of both bones is removed. The chosen implant (GAM or allograft) is placed in the defect to fill its volume. After the volume has been filled, the tissue is closed in layers.

Results

The results of this primary study have been published in Nature Medicine. In general, the results demonstrate that the gene activated matrices can induce the transfection of wound repair cells and subsequent expression of PTH_1-34. The collagen controls formed no bridging bone except in one case and the allografts demonstrated variable healing. A number of the PTH gams did demonstrate bridging of the defects and effective long term remodeling to competent bone.