Neovascularization and Neoinnervation of Subcutaneously Placed Nucleus Pulposus and the Inhibitory Effects of Certain Drugs

In Brief Study Design. An experimental study in the pig with autologous transfer of nucleus pulpous and retroperitoneal fat to the subcutaneous space of the back. Objectives. To evaluate if there is neovascularization or neoinnervation of subcutaneously placed nucleus pulposus, in comparison to retroperitoneal fat, and under simultaneous treatment by certain antiangiogenetic drugs. Summary of Background Data. It has been suggested that intervertebral discs may be invaded by newly formed blood vessels and nerve fibers following injury of the anulus fibrosus. The nerve fibers have been considered to induce low back pain. However, it is still debated whether such ingrowth may occur and, if present, if this is based on the action of angiogenetic substances in the intervertebral disc or simply by normal would healing. Methods. In the first series, autologous nucleus pulposus and retroperitoneal fat was placed subcutaneously in 3 pigs. In the second series, autologous nucleus pulposus was placed subcutaneously with simultaneous treatment with methotrexate (n = 3), celecoxib (n = 3), doxycycline (n = 3), and infliximab (n = 3). After 7 days, the tissue was collected and processed immunohistochemically for the visualization of blood vessels and nerve fibers. Results. There was a number of blood vessels and nerve fibers in the nucleus pulposus samples, while no vessels were observed in the fat samples. Neither methotrexate nor celecoxib seemed to be able to reduce the ingrowth of blood vessels (neovascularization) or nerve fibers (neoinnervation). Treatment by doxycycline and infliximab markedly reduced both neovascularization and neoinnervation. Conclusions. Subcutaneously placed autologous nucleus pulposus displays an ingrowth of newly formed blood vessels and nerve fibers within 7 days, in contrast to retroperitoneal fat. Such ingrowth seems to be reduced by doxycycline and infliximab, 2 cytokine inhibitors. The data suggest that the ingrowth may be induced by bioactive substances within the nucleus pulposus. The clinical importance of these data has yet to be elucidated. It has been suggested that newly formed nerve fibers that invade the intervertebral disc following injury to the anulus fibrosus may induce low back pain. In the present study, it was shown that subcutaneously placed nucleus pulposus is invaded by newly formed blood vessels and nerve fibers within 7 days, and that such ingrowth may be blocked by cytokine inhibitors. The clinical importance has to be further elucidated.