Rajagopal Karthikeyan, Schaer Thomas P, Meadows Kyle D, Boyes Madeline, Hilliard Rachel, O'Donnell John C, Dodge George R, Petrov Dmitriy, Elliott Dawn M, Mauck Robert L, Smith Lachlan J, Malhotra Neil R
Translational Musculoskeletal Research Center Corporal Michael J. Crescenz VA Medical Center Philadelphia Pennsylvania USA.
Department of Orthopaedic Surgery Perelman School of Medicine, University of Pennsylvania Philadelphia Pennsylvania USA.
JOR Spine. 2025 May 27;8(2):e70076. doi: 10.1002/jsp2.70076. eCollection 2025 Jun.
Intervertebral disc degeneration is strongly implicated as a cause of low back pain. Although the precise pathophysiological mechanisms remain elusive, perturbations in nutrition that adversely impact the cellular microenvironment of the central nucleus pulposus (NP) may be contributing factors. A comprehensive understanding of this microenvironment, including changes in nutrient availability as a function of degeneration, is critical for the development of effective cell-based treatments. The goal of this study was to adapt brain tissue oxygen probes and microdialysis catheters for in situ determination of relative NP oxygen, glucose, and lactate levels in a preclinical goat model of disc degeneration.
Following ex vivo technical refinement in bovine caudal discs, baseline metabolite measurements were performed in vivo in the lumbar discs of 3 large frame goats. Degeneration was then induced via injection of chondroitinase ABC (ChABC) into the NP, and measurements were repeated after 12 weeks. Degeneration severity was graded using magnetic resonance imaging (MRI) and histology, and vertebral endplate porosity was assessed using microcomputed tomography.
Oxygen and lactate levels in goat NPs were significantly higher in degenerate compared to healthy discs, while glucose levels were not significantly different. ChABC-injected discs exhibited higher vertebral endplate porosity, worse histological and MRI grades, and a spectrum of cartilage endplate damage compared to healthy discs. There were significant positive correlations between MRI grade and both NP oxygen and lactate levels.
We successfully adapted techniques including surgical placement, equilibration time, flow rate, and detection method for in situ measurement of oxygen, glucose, and lactate in a goat model of disc degeneration. Interestingly, while increased lactate with degeneration was expected, increased oxygen levels were unexpected. Our findings may, in part, be explained by associated alterations in disc and endplate structure, and motivate future studies to comprehensively establish the underlying mechanisms in this model.
椎间盘退变被强烈认为是下腰痛的一个原因。尽管确切的病理生理机制仍不清楚，但营养方面的紊乱对中央髓核（NP）的细胞微环境产生不利影响，可能是促成因素。全面了解这种微环境，包括营养物质可用性随退变的变化，对于开发有效的基于细胞的治疗方法至关重要。本研究的目的是将脑组织氧探针和微透析导管进行改造，用于在椎间盘退变的临床前山羊模型中对NP的相对氧、葡萄糖和乳酸水平进行原位测定。
在牛尾椎间盘进行体外技术改进后，对3只大体型山羊的腰椎间盘进行了体内基线代谢物测量。然后通过向NP注射软骨素酶ABC（ChABC）诱导退变，并在12周后重复测量。使用磁共振成像（MRI）和组织学对退变严重程度进行分级，并使用微型计算机断层扫描评估椎体终板孔隙率。
与健康椎间盘相比，退变山羊NP中的氧和乳酸水平显著更高，而葡萄糖水平无显著差异。与健康椎间盘相比，注射ChABC的椎间盘表现出更高的椎体终板孔隙率、更差的组织学和MRI分级以及一系列软骨终板损伤。MRI分级与NP氧和乳酸水平之间存在显著正相关。
我们成功地对包括手术放置、平衡时间、流速和检测方法在内的技术进行了改造，用于在山羊椎间盘退变模型中对氧、葡萄糖和乳酸进行原位测量。有趣的是，虽然随着退变乳酸增加是预期的，但氧水平增加却出乎意料。我们的发现可能部分由椎间盘和终板结构的相关改变来解释，并促使未来的研究全面确定该模型中的潜在机制。
