Factors affecting small molecule transport into the intervertebral disc

Abstract

To investigate how alterations to the vertebral endplate vasculature can influence diffusion into the disc, New Zealand White rabbits were administered two contrasting drugs, nimodipine (to enhance the vasculature), and nicotine (to diminish the vasculature) for 8 weeks. Diffusion into the disc was quantified using post-contrast enhanced MRI and alterations to the vasculature were assessed via standard paraffin histology. Our results illustrated that the drugs did affect the endplate vasculature and diffusion, but not as expected - there was no simple correlation between the number of vessels and diffusion into the disc. Chronic nimodipine treatment resulted in an 8.4% to 14.7% increase in diffusion into the disc, which was associated with increases in vessel area and vessel contact with the cartilage endplate.

In conclusion, with this work we have demonstrated two methods for enhancing net transport into both healthy and degenerative discs in vivo. If disc degeneration and low back pain are associated with a reduction in disc nutrition, then methods for enhancing nutrient transport into the disc could be therapeutic. This work can aid in the development of new drugs and physical therapy regimens to slow, prevent or reverse degeneration in patients suffering from low back pain.

We also investigated the effects of dynamic mechanical loading on transport into both healthy and degenerated intervertebral discs in vivo. In animals with healthy discs, transport of a small molecule MRI contrast agent was quantified via post-contrast enhanced MRI following in vivo application of either 2.5, 5, 10, 15 or 20 minutes of low rate axial compression and distraction loading. The effects of high rate versus low rate loading on net transport were also assessed in healthy discs. In animals where degeneration of the disc was induced via needle puncture, disc transport was quantified following either 2.5, 5 or 10 minutes of low rate loading. Our results illustrate that transport into the disc is dependent on the rate of applied loading - high rate loading restricts transport into the disc while low rate loading enhances transport. Low rate loading significantly enhanced net transport into healthy and degenerated discs by a maximal 16.8% and 12.6%, respectively. We have also shown for the first time that the kinetics of contrast agent uptake and clearance are accelerated with low rate loading, and are further accelerated in degenerated versus healthy discs.

Low back pain is a serious social and economic issue, affecting up to eighty percent of the United States population in their lifetime. It is the leading cause of disability in the country, and is associated with an estimated yearly $190 billion in medical costs and lost wages. The most common cause of low back pain is degeneration of the intervertebral disc. The intervertebral disc is a unique in that it is the largest avsascular structure in the body, and relies on transport from the microvessels in the adjacent vertebral endplate to receive nutrients and expel waste products. While disc degeneration is a complex and multifactorial process, a compromise in disc nutrition is widely considered to be a significant contributor to the degenerative cascade. Therefore, the goal of this work was to elucidate mechanisms for enhancing net transport into the intervertebral disc in vivo. We hypothesized that net transport into the intervertebral disc could be increased by (1) increasing diffusion into the disc by augmenting the vasculature of the vertebral endplate region via an angiogenic drug and (2) augmenting diffusion with convection induced by cyclic mechanical compression of the intervertebral disc.