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Biologics for Intervertebral Disk Regeneration and Repair
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Low back and neck pain is ubiquitous and is a prevalent disabler of persons of working age. In fact, more than 100 million work days are lost for this reason every year in the United States, second only behind the common cold. Current treatment for axial pain and intervertebral disk (IVD) degeneration is dominated by symptomatic care such as activity modification, physical therapy, and oral medications. When symptoms are recalcitrant to conservative measures, surgery may be considered. At this time nearly all surgical treatment for predominantly diskogenic axial pain involves removal of the diseased disk, followed by either fusion or metallic disk replacement. No clinically available medical, biologic, or cellular-based treatment is available to slow, halt, or reverse disk degeneration.
IVD degeneration is characterized by a progressive alteration in the mechanical properties, cellular numbers and composition, nutrition, and metabolic profile. Currently, most biologic strategies for treatment of IVD degeneration are centered on one or more of these aspects of the degenerative cascade. Techniques studied have included augmenting trophic factors either by introduction of growth factors or gene-based therapy to transfect native cells to upregulate growth factor production. This chapter reviews the animal models and advances made in the biologic therapeutic options for disk degeneration.
Animal Models
The study of any intervention for a human disease often requires the development and validation of an animal model equivalent. Several models currently exist, although most can be placed into three major groups: mechanical compression model, annular injury model, and environmental model.
Mechanical Compression Model
Repetitive supraphysiologic mechanical stress has been suggested as a promoter of IVD degeneration. Studies of truck drivers suggested an increased rate of IVD degeneration. Lotz and colleagues devised an animal model of IVD degeneration by placing a static compressive load across a mobile tail segment in a mouse and demonstrated “number of harmful responses in a dose-dependent way: disorganization of the an[n]ulus fibrosus; an increase in apoptosis and associated loss of cellularity; and down regulation of collagen II and aggrecan gene expression.” Another group used a custom-made external loading device to compress rabbit IVD to yield histologic and radiographic evidence of degeneration. This degeneration was not reversible when the compression was removed for 28 days.
Annular Injury Model
Annular injury that initiates the degenerative cascade is a well-known clinical entity. Research has even suggested that a misplaced needle for anterior cervical level confirmation can lead to iatrogenic degeneration. One of the most widely used animal models for disk degeneration is an annular stab model. Sobajima and associates characterized a rabbit model using a 16-gauge needle puncture of the annulus fibrosus (AF) by magnetic resonance imaging (MRI), plain radiographs, histology, and molecular composition. This technique has been adapted to use a percutaneous, minimally invasive stab model with computed tomography (CT) guidance, thus eliminating a formal surgical approach. A more recent study used a similar approach but with the annular injury provided by diode laser. A similar rate of degeneration was seen compared with needle puncture. Despite their widespread use in basic science and translational research, the annular injury model has been criticized as perhaps not truly reflecting age-related IVD degeneration, and it may more accurately represent posttraumatic disk degeneration.
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