Animal models to study spinal intervertebral disc phenotypes

Introduction

Animal models are important for understanding disease mechanisms and also serve as a central component of preclinical evaluation of treatments for intervertebral disc (IVD) degeneration-related back pain. Factors, such as physical stress, solute transport, immunity, and tissue spatial relationships undoubtedly influence the manner by which animal IVDs degenerate, either spontaneously with age or after induction with mechanical or chemical insult. Equally important are the phenotypic behaviors of IVD cells that may be species-specific and therefore different from human IVD cells. Therefore, while animal models are an important and necessary bridge between in vitro systems and human clinical studies, they must be applied and interpreted with thoughtful consideration of their limitations and relevance to the particular line of investigation.

A primary obstacle in using animal models for IVD degeneration/regeneration research is whether clinically relevant pathologies exist or can be induced. This is particularly important when testing IVD regenerative therapies, where a primary goal is to determine whether the product (cells, matrices, and/or growth factors) can stimulate a desirable disease-modifying activity within the inhospitable niche of the degenerating human IVD [ ]. If the disease model does not sufficiently mimic the human situation, then animal data may not reasonably forecast future clinical trial outcomes. This fact underscores the importance that the chosen animal model simulates the salient pathological, technical, and clinical features. The larger the discrepancy between the animal model and humans, the greater the risk that the therapy will be ineffectual or even harmful. This difficultly is compounded by the fact that we are still uncovering human IVD pain mechanisms and hence have not fully defined the desired disease-modifying activities for new therapies.

Many animal models have been investigated in attempts to clarify disease mechanisms [ ]. However, these are not necessarily appropriate for judging the quality of a regenerative response. Similarly, there is a diversity of animal models used for preclinical testing of bioactive IVD therapies [ ]. Yet, significant gaps between outcome measures in animals and pain mechanisms in humans muddle decision-making when designing preclinical studies. The purpose of this review is to summarize factors that should be weighed when considering an animal model for degeneration research or therapy development and validation.

Anatomy

Across the various species used for spine research, the IVD comprises the same basic subtissues: nucleus pulposus (NP), annulus fibrosus (AF), and cartilage endplate ( Figs. 4.1 and 4.2 ) (see Chapter 1 ). This is not surprising given the similar developmental origins and functional requirements to facilitate spine flexibility while supporting the load. However, species diversity, principally in size and bipedalism, leads to differences that can become significant in the context of IVD degeneration research and tissue engineering.