Low back pain is often associated with degeneration of the intervertebral disc (IVD) and represents the most common physical condition for which patients visit their doctor. There are currently no acceptable biomaterials available to repair small annulus fibrosus (AF) defects of the IVD that might be associated with needle injection of biologics or discography, discectomy procedures for herniations, or other small lesions and AF tears. These types of defects are linked with accelerated IVD degeneration. The overall goal of this training grant is to evaluate fundamental biomechanics and biology associated with the development of promising biomaterial sealants for small AF repairs. The success of a sealant for AF repair depends on its mechanical properties, cytocompatibility, and its ability to function in a complex mechanical and chemical environment in situ. This training grant involves mechanical and biological assessments of AF tissue sealants and their interactions with native AF tissue in order to optimize the biomaterial in vitro and to evaluate the biomaterial in situ. Effective AF sealants must be designed to have tunable material properties, promote cell infiltration, have strong adhesive capabilities, and be injectable to fill a variable range of defets. The two gels proposed are a genipin cross- linked fibrin gel (fib-gen) and carboxymethylcellulose hydrogel (CMC). The in vitro optimization (Aim 1) is comprised of testing multiple sealant formulations of each gel in shear to match the mechanical stiffness of native bovine AF tissue, to create strong adhesive properties in bilayered constructs with native bovine AF, and to promote cell viability and cell proliferation on cell-seeded gels. The in situ assessments (Aim 2) are to assess the sealant-tissue interface at the microscale level using a novel confocal microscopy imaging technique under loading, to evaluate mechanical restoration of biaxial mechanical properties in a vertebral motion segment following repair, and to assess the sealant-tissue interface for cell growth and transport using organ culture techniques. The overall hypothesis is that an AF adhesive sealant can be optimized to be cytocompatible, of comparable mechanical strength as native AF tissue, and capable of restoring biomechanical behaviors of injured motion segments to the uninjured state. The proposed aims of this research strategy complement a training plan comprised of training modules that include Biomaterials Characterization and Development (with CMC and fib-gen formulation), Cell and Molecular Biology (with cell viability and proliferation testing), Microscopy and Imaging (with microscale imaging and strain mapping of adhesive and tissue interfaces), and Clinical and Translational Research (with application of clinically relevant defects and delivery of repair).
Intervertebral disc degeneration is thought to play a major role in the manifestation of low back pain. This training grant will develop, optimize and evaluate novel hydrogel biomaterials for their use as sealants to be used in minimally invasive surgical interventions for pathological conditions of the IVD. Training goals that complement the scientific aims allow the applicant to develop novel and important new technical skills that expand and build off her prior biomedical engineering background to prepare her for an independent research career.
|Guterl, C C; See, E Y; Blanquer, S B G et al. (2013) Challenges and strategies in the repair of ruptured annulus fibrosus. Eur Cell Mater 25:1-21|