A Review of Preclinical Program Development for Evaluating Injectable Carriers for Osteogenic Factors

Recombinant human bone morphogenetic protein-2 (rhBMP-2) delivered with an absorbable collagen sponge (ACS) has been used to both accelerate and ensure healing of open tibial fractures in human patients 1,2. Recombinant human osteogenic protein-1 (rhOP-1, rhBMP-7) delivered with type-1 bovine bone-derived collagen has also been used to treat tibial nonunions in patients 3. A major limitation of both of these biomaterials is the requirement for open surgical placement, which prevents treatment of patients with a closed fracture managed by closed reduction. This represents a substantial patient population, since closed fractures constitute the vast majority of the 6.3 million fractures seen annually in the United States 4. Development of an injectable carrier for osteogenic factors would allow treatment of closed fractures and would also overcome several other limitations of current implantable carriers. Placement of implantable products during the repair of open long-bone fractures is generally limited to areas of exposed bone caused by the injury, which often are not ideal environments for healing. For example, the anteromedial surface of the bone is typically exposed in open tibial fractures, and there is minimal soft tissue for interaction with osteogenic factors placed in this location. Elevation of normal muscle attachments to create a space for more optimal placement of implantable osteogenic factors is often not done because of the risk of further compromising the already damaged blood supply to the fractured bone. In contrast, injectable formulations could be delivered to these more advantageous sites with no additional soft-tissue exposure. Implantable products are also difficult to place into the sites of metaphyseal fractures, as access to these sites is sometimes limited. The increased use of minimally invasive surgical techniques further limits the utility of implantable osteogenic factor formulations. As a result, considerable clinical benefit would be derived from the …