Background: Tissue sources of pain emanating from degenerative discs remains incompletely understood. Canine intervertebral discs (IVDs) were needle puncture injured, 4-weeks later injected with either phosphate-buffered saline (PBS) or NTG-101, harvested after an additional fourteen weeks and then histologically evaluated for the expression of NGFr, BDNF, TrkB and CALCRL proteins. Quantification was performed using the HALO automated cell-counting scoring platform. Immunohistochemical analysis was also performed on human IVD tissue samples obtained from spinal surgery. Immunohistochemical analysis and quantification of neurotrophins and neuropeptides was performed using an in vivo canine model of degenerative disc disease and human degenerative disc tissue sections. Discs injected with NTG-101 showed significantly lower levels of Nerve Growth Factor receptor (NGFr/TrkA, p = 0.0001), BDNF (p = 0.009), TrkB (p = 0.002) and CALCRL (p = 0.008) relative to PBS injections. Human IVD tissue obtained from spinal surgery due to painful DDD show robust expression of NGFr, BDNF, TrkB and CALCRL proteins. A single intradiscal injection of NTG-101 significantly inhibits the expression of NGFr, BDNF, TrkB and CALCRL proteins in degenerative canine IVDs. These results strongly suggest that NTG-101 inhibits the development of neurotrophins that are strongly associated with painful degenerative disc disease and may have profound effects upon the management of patients living with discogenic pain.

Study Design.: Multicenter, concurrently controlled Food and Drug Administration Investigational Device Exemption trial. Objective.: To test the hypothesis that decompression combined with a dynamic sagittal tether (D+DST) was a safe and effective noninferior alternative to decompression and transforaminal lumbar interbody fusion (D+TLIF) for patients with degenerative spondylolisthesis (DS) and stenosis. Summary of Background Data.: Instability leading to symptom recurrence in patients undergoing decompression alone for DS is a concern, resulting in many patients receiving decompression and fusion. An alternative was developed incorporating decompression with stabilization using a dynamic sagittal tether to restore flexion stability and facet joint engagement, reducing segmental translation. Methods.: Patients with Grade I DS+stenosis amenable to decompression were recruited. Outcomes included composite clinical success (CCS), leg/hip and back pain, Oswestry Disability Index (ODI), reoperations, and radiographic measures. CCS was defined as: successful implantation, no reoperation at index or adjacent levels, minimum 15-point ODI improvement, no device failure, and no neurologic decline unless attributable to unrelated cause. A propensity score (PS) model was developed using 25 preoperative covariates to achieve balance and control for bias. Results.: 287 patients were PS-selected (140 D+DST; 147 TLIF). D+DST demonstrated significantly lower operative time, blood loss, and hospital stay. CCS rates were 78.8% with D+DST and 61.2% with D+TLIF, with a PS-adjusted difference of +10.4% favoring D+DST, meeting the primary noninferiority endpoint. Leg/hip pain, back pain, and ODI scores significantly reduced in both groups. Angular motion and segmental translation were both reduced 24% after D+DST and by 68% and 77%, respectively, after D+TLIF. Angular and translational motion at the supradjacent level were significantly greater after D+TLIF, and statistically unchanged following D+DST. Index or adjacent level reoperation rates were 7.2% after D+DST and 9.8% after D+TLIF. Conclusions.: D+DST was noninferior to D+TLIF at 2 years, supporting its effectiveness in treating Grade I DS+stenosis.