Abstract:

Intervertebral disc herniation is a highly prevalent orthopedic disorder, and intervertebral disc degeneration (IDD), the key pathological basis, is a complex pathological process characterized by progressive degradation of extracellular matrix, structural failure, and loss of biomechanical function, which not only shows higher prevalence in the population, but is also the primary cause of chronic low back pain and dysfunction worldwide, causing a huge socioeconomic burden. Although constructing IDD animal models is important for exploring the pathological mechanisms and promoting translational research of this disease, the etiology and pathophysiological mechanisms of IDD have not been fully elucidated. There are significant differences between humans and common laboratory animals in spinal anatomy, biomechanics, and degenerative course, coupled with the diversity and lack of unified standards of existing IDD animal models. This guide systematically reviews IDD animal models of rodents, non-human primates, as well as different species such as rabbits, goats/sheep, pigs, and dogs, focusing on the modeling principles of three main types of models: inducible models (such as annulus fibrosus/nucleus pulposus/endplate injury and mechanical injury) are suitable for simulating acute injury and rapid screening of therapies due to their high controllability and short cycle; spontaneous models can better simulate the age-related natural degeneration process in humans; genetically modified models provide powerful tools for analyzing specific molecular pathways. The guideline deeply analyzes the key technical points, reproducibility, and clinical relevance of these models. It also compares their advantages, limitations, and applicable research scenarios to guide researchers to conduct "scientific question-driven" precise model selection. Meanwhile, to improve the depth and comparability of research results, this guideline proposes a multidimensional endpoint evaluation system for IDD animal model experiments covering imaging, histology, biochemistry/molecular biology, biomechanics, and pain-related behavior, with recommended observation time windows. It also clarifies the "3Rs (replacement, reduction, and refinement)" ethical principles and animal welfare requirements throughout the experiment. In addition, the guideline outlines future research directions such as integrating single-cell omics, multiscale mechanical analysis, and strengthening pain-related phenotype assessment. This guideline aims to provide researchers with a systematic and standardized methodological framework for the rational selection and application of IDD animal models under specific scientific questions and resource constraints, in order to reduce inter-study heterogeneity, enhance the translation efficiency of preclinical findings, promote high-quality development in the field, and ultimately provide a solid scientific foundation for developing innovative therapies to delay or even reverse IDD.

Key words: Intervertebral disc degeneration, Intervertebral disc herniation, Experimental animal model, Preclinical research, Model evaluation, Cross-species translation