Intervertebral Disk Repair by Protein, Gene, or Cell Injection: A Framework for Rehabilitation-Focused Biologics in the Spine

Abstract

Low back pain carries an enormous socioeconomic burden. Current treatment modalities for symptomatic intervertebral disk (IVD) degeneration have limited and often inconsistent clinical benefits. Novel approaches with the potential to halt or even reverse disk degeneration and restore physiologic disk function, such as biological treatments, are therefore very attractive. The following barriers are impeding the development of successful therapeutic interventions: (1) the biology and pathophysiology of disk degeneration are not well understood, and (2) the precise relationship between IVD degeneration and low back pain remains unclear. This article reviews the structural changes that take place during IVD degeneration and their relationship to diskogenic back pain. It also presents treatment modalities that currently are under laboratory investigation and are being studied in clinical trials. The authors of recent studies have shown that the content of large proteoglycans, such as aggrecan and versican, decreases with aging and IVD degeneration, whereas the content of certain small proteoglycans, such as biglycan, increases. Proinflammatory cytokines such as interleukin-1 and tumor necrosis factor-α also are associated with IVD degeneration and are potential biomarkers of IVD degeneration and repair. Our group of investigators and others have developed in vitro models of IVD cell and explant culture in addition to in vivo animal models to study IVD degeneration and repair. With the use of these models, we have tested candidate therapeutic agents to assess their therapeutic potential for matrix restoration. When a rabbit annular puncture model of IVD degeneration was used, injections of either bone morphogenetic protein-7 (also known as osteogenic protein-1) or bone morphogenetic protein-14 (also known as growth differentiation factor-5) were shown to be effective in restoring IVD structures. On the basis of these data, the Food and Drug Administration has recently allowed the initiation of Investigational New Drug clinical trials on osteogenic protein-1 and growth differentiation factor-5 in the United States. Protein therapies such as other growth factors, inhibitors of degradation enzymes or cytokines, and cell therapies also are being investigated in laboratory settings with the goal of restoring disk function and alleviating back pain symptoms. These therapies may be used by physiatrists with the skills required to administer intradiskal injections and supervise a comprehensive rehabilitation program after the procedures. Ultimately, the clinical use of any biological treatment discussed in this article would require the collective efforts of clinicians and researchers.