2020 Research Grant. Development of a clinically-relevant large animal model of intervertebral disc disease

BACKGROUND CONTEXT Low back pain affects 80% of human population with over 40% of cases attributed to degenerative disc disease (DDD). Many therapeutic strategies for DDD are under investigation worldwide, however, translation to clinic is hampered by lack of an appropriate preclinical animal model. The successful development of a clinically relevant model of intervertebral disc degeneration is essential for developing any meaningful basic or applied science understanding of DDD. PURPOSE We proposed the use of two methods in the sheep spine to achieve an ideal preclinical model of DDD: 1) extracorporeal shock wave therapy (ESWT) focused on the disc and 2) intervertebral disc compression. STUDY DESIGN/SETTING Nine (N=9) sheep were randomly divided in 3 groups. Group A (n=3) received radial ESWT at L2-3 and L4-5 through a lateral retroperitoneal approach. Group B (n=3) mechanical compression was applied at L2-3 and L4-5 using customized, MRI compatible materials. Group C (n=3) were left alone as untreated controls. METHODS Blood serum was collected to evaluate changes in TNF-alpha, IL-1ß, IL-6, IL-10, IL-17A at various timepoints throughout the 12-week study period. MRI and radiographs were performed before intervention and at 6 and 12 weeks to evaluate disc height and Pfirrmann grade. Finally, nondestructive kinematics, glycosaminoglycan evaluation and histological scoring were performed. RESULTS Direct administration of ESWT to the intervertebral disc was well tolerated, and animals displayed no clinical signs of pain throughout the 12-week study period. ESWT did not result in significant changes in Pfirrmann grades or radiographic disc height that were consistent with DDD. Similarly, no significant changes were noted in cytokine levels, glycosaminoglycan levels and histological scores compared with control levels. However, new bone formation was noted at the site of ESWT delivery both macroscopically and histologically. Mechanical compression successfully altered the radiographic disc heights immediately after the application. MR imaging was possible but resulted in moderate metal artifact creation. No differences were noted in Pfirrmann grades from baseline or controls. Compressed levels showed a reduction in kinematic changes consistent with DDD, while no changes were observed in the cytokine levels, glycosaminoglycan levels or histological scores consistent with DDD in animals treated with compression compared to control group. CONCLUSIONS Main limitations of this pilot study are small sample sizes. Future studies will aim to utilize more animals with an extended study timeline. Additionally, use of focused shockwaves instead of radial shockwaves may provide greater depth and focus of energy release within the NP resulting in changes within the disc. Lastly, a compression device completely internal will reduce risk of infection and allow compression over a longer period. To our knowledge this is the first study evaluating use of ESWT or disc compression for development of DDD. Both methods resulted in minimal changes at the disc (new bone formation for ESWT and reduced kinematics for compression) that may be worth evaluating further in future studies. If a larger study can result in significant differences in either model, this would be the first time a model of DDD has been developed without directly causing trauma to the annulus fibrosus tissue making these models more clinically relevant than needle puncture, annulotomy or nucleotomy procedures. FDA Device/Drug Status This abstract does not discuss or include any applicable devices or drugs. Low back pain affects 80% of human population with over 40% of cases attributed to degenerative disc disease (DDD). Many therapeutic strategies for DDD are under investigation worldwide, however, translation to clinic is hampered by lack of an appropriate preclinical animal model. The successful development of a clinically relevant model of intervertebral disc degeneration is essential for developing any meaningful basic or applied science understanding of DDD. We proposed the use of two methods in the sheep spine to achieve an ideal preclinical model of DDD: 1) extracorporeal shock wave therapy (ESWT) focused on the disc and 2) intervertebral disc compression. Nine (N=9) sheep were randomly divided in 3 groups. Group A (n=3) received radial ESWT at L2-3 and L4-5 through a lateral retroperitoneal approach. Group B (n=3) mechanical compression was applied at L2-3 and L4-5 using customized, MRI compatible materials. Group C (n=3) were left alone as untreated controls. Blood serum was collected to evaluate changes in TNF-alpha, IL-1ß, IL-6, IL-10, IL-17A at various timepoints throughout the 12-week study period. MRI and radiographs were performed before intervention and at 6 and 12 weeks to evaluate disc height and Pfirrmann grade. Finally, nondestructive kinematics, glycosaminoglycan evaluation and histological scoring were performed. Direct administration of ESWT to the intervertebral disc was well tolerated, and animals displayed no clinical signs of pain throughout the 12-week study period. ESWT did not result in significant changes in Pfirrmann grades or radiographic disc height that were consistent with DDD. Similarly, no significant changes were noted in cytokine levels, glycosaminoglycan levels and histological scores compared with control levels. However, new bone formation was noted at the site of ESWT delivery both macroscopically and histologically. Mechanical compression successfully altered the radiographic disc heights immediately after the application. MR imaging was possible but resulted in moderate metal artifact creation. No differences were noted in Pfirrmann grades from baseline or controls. Compressed levels showed a reduction in kinematic changes consistent with DDD, while no changes were observed in the cytokine levels, glycosaminoglycan levels or histological scores consistent with DDD in animals treated with compression compared to control group. Main limitations of this pilot study are small sample sizes. Future studies will aim to utilize more animals with an extended study timeline. Additionally, use of focused shockwaves instead of radial shockwaves may provide greater depth and focus of energy release within the NP resulting in changes within the disc. Lastly, a compression device completely internal will reduce risk of infection and allow compression over a longer period. To our knowledge this is the first study evaluating use of ESWT or disc compression for development of DDD. Both methods resulted in minimal changes at the disc (new bone formation for ESWT and reduced kinematics for compression) that may be worth evaluating further in future studies. If a larger study can result in significant differences in either model, this would be the first time a model of DDD has been developed without directly causing trauma to the annulus fibrosus tissue making these models more clinically relevant than needle puncture, annulotomy or nucleotomy procedures.