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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.
Environmental Model
Many studies have linked smoking to accelerated rates of IVD degeneration. One study demonstrated that mice exposed to long-term cigarette smoke demonstrate IVD degeneration. This may be a useful model to better understand the pathways linking smoking to IVD degeneration.
Different Treatment Strategies for Different Stages of Disk Degeneration
Different stages of disk degeneration will likely require different treatment strategies. In the early stages of disk degeneration, cells in the nucleus pulposus (NP) area are still abundant. Therefore, a non–cell-based treatment option, such as in vivo gene transfer or growth factor injection targeted at NP regeneration using minimally invasive techniques, may be the most suitable strategy for targeting early disk degeneration.
However, for moderate disk degeneration, most functional NP cells, the target of gene therapy, have already disappeared, so only gene delivery or growth factor injection is insufficient. Thus, ex vivo gene approach or NP tissue engineering will be better for the intermediate stages of disk degeneration.
In the end stages of degeneration, the disk may be virtually nonexistent and replaced with a thin mass of fibrous tissue. Therefore, a tissue-engineered AF, or whole disk, or artificial disk will be needed ( Fig. 47-1 ).
Interventions
The IVD regeneration and repair technology has been developed in three major areas: appliance of growth factors, characterization and use of stem cells, and the development of novel, degradable biomaterials.
Growth Factors
One of the hallmarks of disk generation is the imbalance of the catabolic and anabolic metabolism of extracellular matrix. Thus, scientists are targeting the production of extracellular matrix of disk cells and decreasing the degradation of matrix with growth factors and inhibitors of matrix degrading enzymes. Numerous studies have demonstrated that various growth factors promote disk cell proliferation and glycosaminoglycan synthesis, such as growth differentiation factor-5 (GDF5, also named BMP-14), bone morphogenetic proteins (BMPs), insulin-like growth factor-1 (IGF-1), fibroblast growth factor (FGF), transforming growth factor-β (TGF-β), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and platelet-rich plasma (PRP) ( Table 47-1 ).
| Molecular | Method | Outcome |
|---|---|---|
| BMP-2 | Gene and protein therapy | Increase proteoglycan and collagen production, delay degeneration process |
| BMP-7 | Gene and protein therapy | Increase cell proliferation and proteoglycan synthesis; Restore disk structure and biomechanical function |
| GDF5 | Gene and protein therapy | Increase proteoglycan and collagen synthesis, restore disk height and delay degeneration process |
| IGF-1 | Protein and gene therapy | Enhance proteoglycan synthesis, increase cell proliferation and anti-apoptotic effects; preserve degenerated disk |
| PDGF | Protein therapy | Increase cell proliferation |
| TGF-β1 | Gene and protein therapy | Increase cell proliferation and proteoglycan production in vitro and in vivo |
| bFGF | Protein therapy | Increase cell proliferation |
| Proteinase inhibitor TIMP-1 | Gene therapy | Increase proteoglycan synthesis of human degenerated disk cells; delay degeneration changes in rabbits |
| Sox 9 | Gene therapy | Increase collagen in human degenerated disk cells; main rabbit disk cell chondrocyte phenotype and architecture of the NP |
| Lim mineralization protein-1 | Gene therapy | Increases proteoglycan, BMP2, and BMP7 in cultured cells and disk of rabbit with intradiskal injection |
| Platelet-rich plasma (PRP) | Protein | Increase cell proliferation and matrix production; increase disk height and maintain disk structure |
| TNF inhibitor | Protein | Decrease MMPs level |
| Interleukin-1α receptor | Gene and protein therapy | Decrease MMP3 and ADAMTS-4 expression |
These growth factors can be given by intradiskal injection or delivered with cells or scaffolds. For example, in the cultured disk cells, GDF5 has been shown to promote NP cell proliferation and increase GAG production. Similarly, in a rabbit disk degeneration model, injection of recombinant GDF5 alleviated degenerative progression and restored disk height. Adenovirus GDF5 injection to mice disks increased extracellular protein production and restored disk height and T2-weighted signal in an MRI study ( Fig. 47-2 ).
BMP-7 has also been shown to have a similar function. Indeed, GDF5 and BMP-7 have been approved for a phase I clinical trial of intra-disk injection. The combination of several growth factors can synergistically stimulate matrix synthesis in the disk. In a pilot clinical study, a “cocktail solution” comprising a mixture of agents known to induce the synthesis of proteoglycan was injected into the lumbar disks of 30 patients with chronic low back pain. The evidence clearly showed that growth factors alter the degenerative process in the disk. The response of NP and AF cells may differ in response to growth factors; therefore, optimized combinations of growth factors may be needed for individual patients, depending on cells or metabolic pathways. However, some of these growth factors not only stimulate chondrogenic response but also induce osteogenesis. For example, BMP-2, BMP-7, GDF5, and TGF-β have been shown to have osteogenic properties.
Other proteins such as inhibitors of matrix degrading enzyme or inflammatory cytokines have also been investigated for the disk degeneration. The injection of recombinant interleukin-1 (IL-1) receptor antagonist reversed disk degeneration and restored disk height by inhibiting matrix metalloproteinases (MMPs). Tumor necrosis factor (TNF) inhibitors and antibody have shown promising results as well. The N terminal peptide of Link protein was shown to halt and reverse some of the degeneration in a rabbit disk injury model. Gene therapy methods have also been used to deliver growth factors or inhibitors to the disk space for constant endogenous production and release of the molecules.
Cells
The use of proteins or gene transfer approaches is based on the assumption that enough viable disk cells are available; thus, the protein treatments are not suitable for the moderate stage of disk degeneration, in which the numbers of disk cells that can respond to growth factor and produce matrix are greatly diminished. Three major cell sources have been investigated: autologous disk cells, articular chondrocytes, and mesenchymal stem cells (MSCs) ( Table 47-2 ). Autologous disk cell transplantation demonstrated promising results in rabbit, sand rat, and canine models. In a randomized, multicenter clinical trial, the EuroDisc study, interim 2-year analysis showed safe application and a decreased sum score and disability index in 14 patients who received disk chondrocyte transplantation. However, obtaining the “healthy” disk cells is a challenge, and the survivability of disk cells in the disk tissue is questionable.
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