Predicting the efficacy of therapeutic spinal loading for intervertebral disc regeneration

Philadelphia Va Medical Center, Philadelphia PA

Investigators

Abstract

In Veterans, the most common location of chronic pain is the spine, with back pain frequently caused by intervertebral disc degeneration. The intervertebral discs are unique in that they are the largest avascular structures in the body. Cells within the disc therefore rely primarily on diffusive transport from the vessels and marrow channels in the adjacent vertebral endplate to receive nutrients and expel waste products. Despite the critical role of trans-endplate transport in disc homeostasis, its association with disc degeneration and regeneration remain severely understudied. To date, augmenting trans-endplate transport as a therapeutic strategy for disc regeneration remains largely unexplored compared to traditional tissue engineering or regenerative medicine approaches. The goals of this proposal are therefore to 1). define how compromised intervertebral disc nutrition (i.e. trans-endplate transport of nutrients and waste products to and from the avascular disc) impacts the extent to which therapeutic spinal loading can induce disc regeneration, and 2). to identify biomarkers of disc nutrition predictive of patient response to clinical rehabilitation strategies. To achieve these goals, in Aim 1 we will define how trans-endplate transport is altered as a function of intervertebral disc degeneration severity. Correlations between transport across the boney and cartilage endplate and quantitative measures of disc degeneration will first be established in human cadaveric tissues. Next, a spectrum of disc degeneration and accompanying endplate remodeling will be induced in vivo in a rabbit disc puncture model. Correlations between trans-endplate transport and disc health will also be determined in the rabbit model and matched to human disease states. In Aim 2, we will then utilize this rabbit model to determine the impact of compromised trans-endplate diffusion on the capacity of therapeutic spinal loading to regenerate the disc. First, we will define a non-invasive treadmill exercise routine for rabbits which enhances trans-endplate transport into the discs. This exercise regimen will then be applied in rabbits with degenerative discs with or without compromised trans-endplate transport. Control animals will receive no therapeutic loading, and disc regeneration will be assessed using quantitative measures of disc structure, function, and biology across all experimental groups. Aims 1 and 2 will establish which stages of degenerative disc disease are associated with compromised disc nutrition and whether this impacts the capacity of therapeutic spinal loading to have an anabolic effect on disc health. In human patients with back pain, therapeutic spinal loading may be achieved by exercise or physical therapy, which are effective in relieving pain in some but not all patients. Therefore, in Aim 3 we will identify magnetic resonance imaging and serum biomarkers for impaired disc nutrition in human patients with back pain, and determine if these biomarkers will predict patient response to non-operative treatments for back pain. The proposed research has the potential to contribute significantly to improving rehabilitation strategies for Veterans with back pain, in addition to identifying biomarkers predictive of patient response to treatment.