Low back pain, most commonly caused by degeneration of the intervertebral disc, places a significant social and economic burden on the general public, active duty military and veterans alike. The intervertebral discs of the spine are the largest avascular structures in the body, and the cells within the disc therefore rely on the transport of nutrients and waste products across the vertebral endplate to maintain disc homeostasis. A compromise in transport across the vertebral endplate interface is therefore implicated in the initiation and progression of disc degeneration. The overarching goal of this proposal is twofold: (1) Elucidate the properties of the boney and cartilage endplates that affect trans-endplate transport and how alterations in transport contribute to disc degeneration, and (2) investigate alterations to trans-endplate transport and disc health during non-operative treatment of patients with back pain and their correlation with pain relief and functional outcomes. These goals will be accomplished via the following specific aims:
Aim 1 : Determine the structural, mechanical and compositional properties of the vertebral endplates affecting diffusion and convection into healthy and degenerative human intervertebral discs. A custom MRI-compatible device will be constructed to quantify the transport properties of cadaveric human endplate samples under both diffusion and convection (fluid flow). Transport properties will then be correlated with boney endplate compositional and local mechanical properties, as assayed via CT, histology, Fourier transform infrared spectroscopy (FTIR), local strain tracking analysis, and atomic force microscopy (AFM).
Aim 2 : Establish correlations between intervertebral disc degeneration, trans-endplate small molecule diffusion, and vertebral endplate structure, composition and mechanics in an in vivo rabbit model. Intervertebral disc degeneration will be induced in vivo in a rabbit model via puncture of the disc with a 16G or 21G needle. Animals will be euthanized at 4, 8, and 16 weeks post-puncture to generate a spectrum of degeneration from mild (21G puncture) to severe (16G puncture). Small molecule trans-endplate diffusion into the disc will be quantified via post-contrast enhanced MRI T1-mapping. The boney and cartilage endplates will be assayed via microFil enhanced CT to determine bone and vascular density. Composition and mechanics of the endplates will be assayed via FTIR and AFM, respectively. Degeneration of the intervertebral disc will be assessed via MRI T2-mapping, histology, biochemistry and gene expression assays.
Aim 3 : Determine the feasibility and preliminary outcomes of quantifying the effect of physical therapy on trans-endplate diffusion into the degenerative disc in patients with back pain. Human patients with back pain concomitant with disc degeneration will be subjected to MRI T2- mapping and post-contrast enhanced T1-mapping at time points prior to and 6 weeks after physical therapy. Standard questionnaires of pain (visual analog scale), function (Oswestry Disability Index), as well as objective measures of lumbar range of motion, will be completed at the same time points to establish correlations between disc health, nutrition and patient outcomes.
The research objective of this proposal is to elucidate the role of disc nutrition via the vertebral endplate in the initiation and progression of disc degeneration, and in the response of patients with back pain to non-operative treatment. The proposed research builds on Dr. Gullbrand?s previous research experience in animal models, disc nutrition and imaging, while allowing her to develop new skills and expertise in disc biology and clinical research. The proposed research is complimentary to the objectives of her mentors? VA-funded research efforts in this area. This Career Development Award proposal identifies a mentoring team, career development and research activities that will support Dr. Gullbrand in transitioning towards a position as an independent VA investigator.
