Elsevier

The Spine Journal

Volume 5, Issue 6, Supplement, November–December 2005, Pages S209-S216
The Spine Journal

I. Spinal Fusion
Animal models for spinal fusion

https://doi.org/10.1016/j.spinee.2005.02.013Get rights and content

Abstract

Animal models for spinal fusion are essential for preclinical testing of new fusion methods and adjuncts. They allow for control of individual variables and quantification of outcome measures. Model characteristics are considered. Preclinical experiments to evaluate proof of concept, feasibility, and efficacy are generally studied in an orderly progression from smaller to larger animal models with an evolving cascade of evidence which has become known as the “burden of proof”. Methods of fusion analysis include manual palpation, radiographs, computed tomography, histology, biomechanical testing, and molecular analysis. Models which have been developed in specific species are reviewed. This sets the stage for the interpretation of studies evaluating bone graft materials such as allograft, demineralized bone matrices, bone morphogenetic proteins, ceramics, and others with consideration of the variables affecting their success. As evidence accumulates, clinical trials and applications are defined.

Introduction

Spine fusion is a common surgical procedure which is performed for a number of conditions including degenerative, traumatic, and oncologic pathologies. Crucial to a successful fusion is bone graft material which is potentially osteogenic, osteoinductive, and osteoconductive.

Autograft has long been the “gold standard” bone graft material, but this is clearly associated with morbidities and limitations [1], [2]. For this reason, there is much interest in developing alternative bone graft materials. These would ideally help facilitate more rapid and robust fusion with less morbidity and higher success. Each potential product, however, must be established as safe and effective before entering the clinical arena.

Preclinical animal studies are the primary means of achieving this goal. Such work dates back to Albee's dog experiments in 1913 which are considered the first utilization of an animal model to study spine fusion [3]. This work assessed dorsal (“posterior”) canine fusions at the macroscopic and microscopic level. From this point, many spinal fusion studies using animals have been performed.

To interpret the results of preclinical animal studies, animal models must be well characterized. Methods must be clearly described, and control group data should be established and reproducible from experiment to experiment and from laboratory to laboratory. Only with such standards can quantitative and qualitative experimental outcomes be compared to established norms and contrasted to other related studies. If encouraging results are found in small animal models (rats, mice, rabbits), investigations are generally pursued in higher phylogenetic species (dogs, sheep, goats, pigs) along the path towards nonhuman primates and ultimately to clinical trials.

Initially, studies were performed in whatever species were accessible and cost-effective for given laboratories. However, over time certain species have become more characterized for given study objectives than others [4]. The goal of this review is to elucidate strengths and deficiencies of specific animal models.

Section snippets

Model characteristics

Suitable animal models should mimic the human scenario being evaluated. This means that the anatomy and methodology must be similar to that seen clinically. Intertransverse fusions, for example, can be performed in most species. However, interbody fusions require large, predictable, and parallel end plates as seen only in larger animals. Other models are specifically designed for specific approach techniques. For example, endoscopic and thorascopic models have been described in pigs, sheep, and

Burden of proof

A great number of different species in the spectrum of rats to nonhuman primates have been used to study spinal fusion. Nonhuman primates are obviously most closely related to humans based on size, upright posture, genetic makeup, and so forth, and are accordingly considered the most valid and critical preclinical model. Nevertheless, smaller animal models have many advantages, as described above.

It is generally accepted that researchers must develop a cascade of preclinical experiments that

Review of specific species used for spine fusion models

A number of animal models are used to study spinal fusion, as summarized in Table 1. A number of bone graft products have been tested in such models. This list includes autograft, allograft, demineralized bone matrix, bone morphogenetic protein (BMP) [32], [33], [34], ceramics [25], [32], and recombinant genetic products [35], [36]. Additionally, a number of other variables affecting fusion results have been assessed. This list includes instrumentation [37], [38], motion [8], exposure to

Summary

Overall, animal spine fusion studies are crucial for preclinical evaluation of new fusion methods and adjuncts. The above sections briefly review model characteristics and variables relevant to specific species. In the cervical spine, goats are most frequently studied. In the lumbar spine, where posterolateral studies are most commonly reported, rabbits, sheep, and dogs are most frequently studied. In the thoracic spine, which is a less studied region of the spine, trends are less well

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