The goal of this study is to provide a safe, effective system for inducing bone formation for spine fusion and eliminate the need for invasive surgery. We seek to develop an injectable material that will remain at the injection site and continually induce rapid bone formation until the newly formed bone specifically eliminates the material, effectively turning off the system. Our previous work has led to the development of an inert material that when added to cells expressing a bone producing factor, encapsulates them so that they do not cause a reaction when placed in the body but allow for the secreted factor to diffuse out of the material.

Studies in mice using this material show that we can induce rapid endochondral bone formation at an adjacent site. We propose in this study to modify our current material to add significant versatility, efficacy, and safety to the system. These proposed changes include the use of a gene delivery vector that is regulated, so that expression of the bone-promoting factor will be turned on and off in the presence of the drug tetracycline and thus highly controlled. This adds significant safety, because the protein can be rapidly added or turned off at the bone formation site as needed. Further, after the newly formed bone reaches an adequate size for spine fusion, the cells within it will then start to degrade and eliminate the injected hydrogel encapsulated cellular material, thus avoiding any long-term reactions that might occur with leaving the implanted system in place.

This set of proposed experiments will provide significant knowledge to the field of bone tissue engineering. Proposed studies will provide essential biological information about the cellular processes that the body undergoes to generate rapid vascularized bone. These studies will also allow us to determine the optimal amount of expression time and any spatial requirements for the bone induction protein to achieve spine fusion. The studies also make use of a novel biomaterial that can safely house the cells expressing the bone inductive factor in order to prevent diffusion throughout the body, and also protect against immune reaction and/or other adverse reactions. We propose to modify our current material by including specific molecules that can be recognized by osteoclasts in the new bone and target the material for elimination by normal bone remodeling processes. By elimination of the foreign material, any potential long-term complications will be avoided. Finally, these studies also propose testing the bone formation to confirm true spine fusion in a preclinical murine model, using several biomechanical and radiological criteria.

Ultimately, this system has significant applicability. Surgery of the spine to fuse the vertebral bones is one of the most commonly performed operations with an estimated 350,000 Americans undergoing this procedure annually. The treatment of this disease in the United States is estimated to exceed $60 billion annually in health care costs, which does not include the indirect economic losses associated with lost wages and decreased productivity. Spine fusion is useful for the treatment of deformities, such as scoliosis, instability, and painful degenerative conditions of the spine. As currently performed, it is highly invasive and has a significant failure rate. Often bone must be surgically removed from the pelvis to implant in the spine for proper healing, which requires additional surgery. This additional surgery often results in significant pain and long-term healing. We propose in these studies to complete the necessary modifications and test this system in preclinical murine model. Completion of this study in approximately 4 years would provide us with the necessary data to initiate filing of an Investigation New Drug application with the Food and Drug Administration and allow for the design of a tentative phase I clinical trial. Validation of our hypothesis will provide a safe and efficacious material for the production of bone leading to spine fusion, circumventing the need for bone grafts, or for direct administration of cells, viruses, or other materials that could lead to significant adverse reactions.