Oehme David, Ghosh Peter, Goldschlager Tony, Itescu Silviu, Shimon Susan, Wu Jiehua, McDonald Courtney, Troupis John M, Rosenfeld Jeffrey V, Jenkin Graham
The Ritchie Centre, MIMR-PHI Institute, Monash University, Clayton, Victoria;
Proteobioactives, Pty Ltd, Brookvale, New South Wales;
J Neurosurg Spine. 2016 May;24(5):715-26. doi: 10.3171/2015.8.SPINE141097. Epub 2016 Jan 22.
OBJECTIVE Disc degeneration and associated low-back pain are major causes of suffering and disability. The authors examined the potential of mesenchymal precursor cells (MPCs), when formulated with pentosan polysulfate (PPS), to ameliorate disc degeneration in an ovine model. METHODS Twenty-four sheep had annular incisions made at L2-3, L3-4, and L4-5 to induce degeneration. Twelve weeks after injury, the nucleus pulposus of a degenerated disc in each animal was injected with ProFreeze and PPS formulated with either a low dose (0.1 million MPCs) or a high dose (0.5 million MPCs) of cells. The 2 adjacent injured discs in each spine were either injected with PPS and ProFreeze (PPS control) or not injected (nil-injected control). The adjacent noninjured L1-2 and L5-6 discs served as noninjured control discs. Disc height indices (DHIs) were obtained at baseline, before injection, and at planned death. After necropsy, 24 weeks after injection, the spines were subjected to MRI and morphological, histological, and biochemical analyses. RESULTS Twelve weeks after the annular injury, all the injured discs exhibited a significant reduction in mean DHI (low-dose group 17.19%; high-dose group 18.01% [p < 0.01]). Twenty-four weeks after injections, the discs injected with the low-dose MPC+PPS formulation recovered disc height, and their mean DHI was significantly greater than the DHI of PPS- and nil-injected discs (p < 0.001). Although the mean Pfirrmann MRI disc degeneration score for the low-dose MPC+PPS-injected discs was lower than that for the nil- and PPS-injected discs, the differences were not significant. The disc morphology scores for the nil- and PPS-injected discs were significantly higher than the normal control disc scores (p < 0.005), whereas the low-dose MPC+PPS-injected disc scores were not significantly different from those of the normal controls. The mean glycosaminoglycan content of the nuclei pulposus of the low-dose MPC+PPS-injected discs was significantly higher than that of the PPS-injected controls (p < 0.05) but was not significantly different from the normal control disc glycosaminoglycan levels. Histopathology degeneration frequency scores for the low-dose MPC+PPS-injected discs were lower than those for the PPS- and Nil-injected discs. The corresponding high-dose MPC+PPS-injected discs failed to show significant improvements in any outcome measure relative to the controls. CONCLUSIONS Intradiscal injections of a formulation composed of 0.1 million MPCs combined with PPS resulted in positive effects in reducing the progression of disc degeneration in an ovine model, as assessed by improvements in DHI and morphological, biochemical, and histopathological scores.
目的 椎间盘退变及相关的下腰痛是导致痛苦和残疾的主要原因。作者研究了间充质前体细胞（MPCs）与戊聚糖多硫酸盐（PPS）混合制剂在绵羊模型中改善椎间盘退变的潜力。方法 对24只绵羊在L2 - 3、L3 - 4和L4 - 5节段进行环状切口以诱导退变。损伤12周后，向每只动物退变椎间盘的髓核注射ProFreeze和分别含有低剂量（10万个MPCs）或高剂量（50万个MPCs）细胞的PPS混合制剂。每个脊柱相邻的2个损伤椎间盘分别注射PPS和ProFreeze（PPS对照组）或不注射（未注射对照组）。相邻未损伤的L1 - 2和L5 - 6椎间盘作为未损伤对照椎间盘。在基线、注射前和计划处死时获取椎间盘高度指数（DHIs）。尸检后，注射24周后，对脊柱进行MRI以及形态学、组织学和生化分析。结果 环状损伤12周后，所有损伤椎间盘的平均DHI均显著降低（低剂量组降低17.19%；高剂量组降低18.01% [p < 0.01]）。注射24周后，注射低剂量MPC + PPS制剂的椎间盘恢复了椎间盘高度，其平均DHI显著高于PPS注射组和未注射组的DHI（p < 0.001）。虽然注射低剂量MPC + PPS的椎间盘Pfirrmann MRI椎间盘退变评分低于未注射组和PPS注射组，但差异不显著。未注射组和PPS注射组的椎间盘形态学评分显著高于正常对照椎间盘评分（p < 0.005），而注射低剂量MPC + PPS的椎间盘评分与正常对照组无显著差异。注射低剂量MPC + PPS的椎间盘髓核中糖胺聚糖的平均含量显著高于PPS注射对照组（p < 0.05），但与正常对照椎间盘糖胺聚糖水平无显著差异。注射低剂量MPC + PPS的椎间盘组织病理学退变频率评分低于PPS注射组和未注射组。相应地，注射高剂量MPC + PPS的椎间盘在任何结局指标上相对于对照组均未显示出显著改善。结论 通过DHI以及形态学、生化和组织病理学评分的改善评估，椎间盘内注射由10万个MPCs与PPS组成的制剂对减少绵羊模型中椎间盘退变的进展产生了积极作用。
