Current medical treatments for degenerative disc disease are limited and the available surgical treatments to remove the perturbed discs while stabilizing the new spinal construct are costly and invasive with associated risks of morbidity. Leading research is focused on less invasive methods to reverse or prevent intervertebral disc degeneration. Most rely on costly new drugs and devices. However, new implantations with mobile prostheses or even engineered tissues have brought a new spectrum of complications and hurdles to be addressed. Biological repair or regeneration of the intervertebral disc has been advocated with recent advances in recombinant therapeutic proteins. Many growth factors including bone morphogenetic protein (BMP) have been investigated on the aspect of biological repair and have been proved preliminarily with their anabolic effects on the intervertebral disc cells. Nonetheless, concerns still remain with these recombinant human growth factors since they either participate in undesired blood vessel ingrowth at the intervertebral disc or their given doses are normally much over the physiological levels to obtain effectiveness. In addition, costs for using these biofactors have not yet reached affordable. The proposed study will investigate a treatment for disc degeneration with the potential for substantially lower cost. Our previous work indicated that the common cholesterol-lowing drug simvastatin stimulated endogenous BMP-2 expression and in turn increased the chondrogenic phenotype expression of intervertebral disc cells cultured in vitro, and also the disc degeneration induced by a stab injury was fully reversed when injecting simvastatin that was loaded in a thermosensative, biodegradable polymer into nucleus pulposus of the perturbed discs in our rat model. In this study, we would like to extend our investigation to the defined animal models with IVD degeneration to further characterize the safety and effectiveness of using simvastatin specifically for the treatment of degenerative disc disease as an off-label indication of statins. We hypothesize that controlled release of simvastain from an injectable, degradable polymer will retard the progress of disc degeneration and may further regenerate intradiscal tissues. We will use stab injury (annulotomy) perturbation on intervertebral discs at predetermined levels of Sprague-Dawley rat's caudal spine to develop each category of disc degeneration that will be graded according to imaging, morphological and histological assessments. Grades with intact structure of annulus fibrosus will be indicated to the injection with simvastatin loaded in the polymer. Doses of the drug will be administered in an escalating manner and will be last until predetermined sacrifice time points to characterize the optimal dosage as well as the effective duration. Finally, a Yucatan minipig model will be utilized to further evaluate whether perturbed discs can restore the inherent biomechanical functions and anatomical features of interbody space after being treated with simvastatin to provide an insight in the development and implementation of future clinical trials.

Public Health Relevance

A prevalent cholesterol-lowing drug simvastatin has recently been investigated to stimulate bone cells to secrete a growth factor that can augment bone tissue growth. This mechanism is thought to be critical as well for cells in the intervertebral disc to regenerate tissue substances. It is then proposed in this study to observe the potential to inject simvastatin into degenerative disc to retard the progression of degenerative disc disease and also help repair the aberrant tissues.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR056649-04
Application #
8459883
Study Section
Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Panagis, James S
Project Start
2010-06-11
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2015-03-31
Support Year
4
Fiscal Year
2013
Total Cost
$319,086
Indirect Cost
$113,886
Name
University of Michigan Ann Arbor
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Than, Khoi D; Rahman, Shayan U; Wang, Lin et al. (2014) Intradiscal injection of simvastatin results in radiologic, histologic, and genetic evidence of disc regeneration in a rat model of degenerative disc disease. Spine J 14:1017-28
Wang, Lin; Park, Paul; La Marca, Frank et al. (2013) Bone formation induced by BMP-2 in human osteosarcoma cells. Int J Oncol 43:1095-102
Kang, Heesuk; Hollister, Scott J; La Marca, Frank et al. (2013) Porous biodegradable lumbar interbody fusion cage design and fabrication using integrated global-local topology optimization with laser sintering. J Biomech Eng 135:101013-8
Park, Yoon Shin; David, Allan E; Park, Kyung Min et al. (2013) Controlled release of simvastatin from in situ forming hydrogel triggers bone formation in MC3T3-E1 cells. AAPS J 15:367-76
Wang, Lin; Rahman, Shayan; Lin, Chia-Ying et al. (2012) A novel murine model of human renal cell carcinoma spinal metastasis. J Clin Neurosci 19:881-3
Park, Jun-Beom; Zhang, Huina; Lin, Chia-Ying et al. (2012) Simvastatin maintains osteoblastic viability while promoting differentiation by partially regulating the expressions of estrogen receptors ?. J Surg Res 174:278-83
Wang, Lin; Park, Paul; Zhang, Huina et al. (2011) BMP-2 inhibits the tumorigenicity of cancer stem cells in human osteosarcoma OS99-1 cell line. Cancer Biol Ther 11:457-63
Zhang, Huina; Yang, Sushan; Wang, Lin et al. (2011) Time course investigation of intervertebral disc degeneration produced by needle-stab injury of the rat caudal spine: laboratory investigation. J Neurosurg Spine 15:404-13