Both the diagnosis and treatment of discogenic low back pain (LBP) remains controversial. Patients typically present with history of chronic, mechanical LBP worsened by activity characterized by standing and sitting intolerance, somewhat improved with rest. Pain may be referred to the proximal lower extremities without a specific radiculopathy. Radiographic findings include disc space desiccation characterized by loss of T2 signal in the disc and Modic end plate changes on magnetic resonance imaging (MRI). Computed tomography (CT) findings include end plate sclerosis and loss of disc space height. The use of provocative discography to confirm symptomatic disc degeneration remains controversial, but findings include internal disc derangement and concordance of pain. Although most episodes of LBP are self-limited or successfully treated with nonsurgical management, a significant minority of patients develop chronic, debilitating LBP. This patient population typically remains recalcitrant to nonsurgical management including physical therapy and long-acting narcotic therapy as well as pain procedures (such as epidural steroid injections and facet blocks), and they utilize significant health care resources.

The intervertebral disc (IVD) is an avascular fibrocartilaginous structure consisting of an outer annulus fibrosus and an inner nucleus pulosus. The nucleus consists of chondrocytic cells and type II collagen, whereas the annulus has scant fibroblast cells and type I collagen. Cell density in the adult nucleus has been estimated to be between 4 to 8 × 10 ⁶ cells/cc, and it has been postulated that the cell density will self-regulate depending on nutritional supply. The IVD receives its primary blood supply via diffusion from capillaries of the adjacent vertebral bodies, which terminate in the cartilaginous end plate. Native disc cells depend on passive diffusion for nutrient (glucose, oxygen) supply and waste (lactic acid) removal. Consequently, these native disc cells survive in a relatively harsh environment of low nutrition, high lactic acid, and significant biomechanical loading forces. The disc cells of the nucleus produce extracellular matrix (ECM) consisting primarily of proteoglycans, such as aggrecan and versican, within a type II collagen scaffolding. Proteoglycans are hydrophilic molecules with protein stems surrounded by highly negatively charged glycosaminoglycan (GAG) side chains, such as chondroitin sulfate and keratin sulfate. These GAG side chains attract and hold water molecules. Disc degeneration can be conceptualized as a loss of the disc cell’s ability to produce ECM. The subsequent loss of proteoglycans and their GAG side chains results in disc desiccation with increased load on surrounding structures. Ultimately these increased loads lead to the characteristic findings of degenerative disc disease (DDD), including loss of disc height, annular tears, and end plate sclerosis, which further limits blood supply to the disc and increases load on the disc, perpetuating the process. These structural findings can be manifested clinically as LBP. In this scenario, DDD is the ultimate consequence of the chondrocytic disc cell’s inability to maintain ECM.

Mechanical LBP is a multifactorial entity with multiple potential pain generators, including the disc (nucleus and annulus) and the facet joints. The success of any therapeutic intervention is predicated on the accurate diagnosis of a specific pain generator. The diagnosis of discogenic pain remains especially problematic. Standard MRI provides anatomic detail, but without a functional correlation to structural abnormalities. Provocative discography is an invasive procedure whose reliability and reproducibility has been questioned.

Surgical intervention has traditionally been reserved for intractable LBP and has involved fusion of the degenerated segment, generally lumber interbody fusion (anterior [ALIF], lateral [LLIF], and posterior [PLIF] or transforaminal [TLIF]), which removes the pathologic disc but at the cost of disc function, namely motion. Furthermore, this loss of motion places increased biomechanical stresses at levels immediately adjacent to the fused level, increasing the risk of clinically significant adjacent level disease. Minimally invasive fusion techniques have been developed to decrease operative morbidity, but these procedures still involve loss of motion with increased stresses on adjacent levels. Total disc replacement (TDR) was developed to maintain motion and decrease adjacent level stresses, but it still requires near total disc removal via a major surgical approach via a retroperitoneal approach. Several attempts at less invasive and motion-preserving procedures were developed around nucleus replacement devices such as the prosthetic disc nucleus (PDN) or NUBAC, but none were able to successfully complete the Food and Drug Administration (FDA) investigational device exemption (IDE) process. Subsequently, attention turned to disc augmentation and repair procedures, which were developed in an attempt to repair a pathologic disc without sacrificing its structure and function. Disc augmentation involves injecting tissue scaffolding material (i.e., Nucor [silk/elastic polymer], Biostat Biologix [fibrin sealant]) into the disc. Although both Nucor (phase I) and Biostat (phase III) have been used in clinical investigational new drug (IND) trials, no disc augmentation procedure has completed the IND process and received FDA clearance. Following extensive preclinical and animal study, biologic disc repair procedures entered into human clinical trial. Biologic disc repair can be divided into three broad categories: (1) gene therapy, (2) growth factor therapy, and (3) cellular therapy. Growth factor therapy involves the injection of an exogenous protein to increase the native chondrocytic cell’s ECM production by up-regulating the production of anabolic factors or down-regulating catabolic factors. Gene therapy involves the transfer of genetic material via viral vectors in order to boost the disc’s native chondrocytic cell production of ECM. Cell therapy consists of injecting cells (stem cells, cartilage cells, or disc cells) into the disc space in order to augment the native disc’s ability to produce ECM. In general, the major advantage of disc repair procedures is the ability to address the source of mechanical LBP in select patients with DDD in a minimally invasive fashion while preserving revision options. Each of the three biologic disc repair therapies (growth factor, gene, and cellular) has unique strengths and challenges.

Gene therapy has the potential ability to induce long-term changes in anabolic and catabolic cell function that could, ultimately, increase proteoglycan production. But gene therapy requires vectors, generally viral, to transfer genetic material into host cells. Because gene therapy involves the active transfer of genetic material via viruses, there is some inherent risk of mutagenicity or native immune response. Therefore, gene therapy may be more appropriate for potentially life-threatening disorders, such as cystic fibrosus, but, at least initially, it will play a more limited role in chronic, non-life-threatening disorders such as lumbar DDD. To date, there have been no human studies of gene therapy for disc repair.

Growth factor therapy has the potential to metabolically enhance ECM production, at least in the short term. Growth factors are small peptide cytokines with cell regulatory function, which may be anabolic (i.e., transforming growth factor [TGF]-beta, insulin-like growth factor 1 [IGF-1], epidermal growth factor [EGF], platelet-derived growth factor [PDGF], and bone morphogenetic protein [BMP]) or catabolic (i.e., interleukin [IL-1] and tumor necrosis factor [TNF]). Two different growth factors, BMP-7 (OP-1) and BMP-14 (GDF-5), have been used in phase I/II clinical IND trials. The results of these trials have not been published and there is no growth factor therapy that has completed the regulatory process. Use of growth factors for a chronic disease process like DDD, which develops over a period of years, may be limited by their relatively short biologic half-lives (hours or days) and the fact that chondrocytic disc cells undergoing senescence may be unresponsive to exogenous growth factors.

Cellular therapy involves the introduction of exogenous cells—generally chondrocytes, undifferentiated stem cells, or disc cells—to augment native disc cells that produce ECM. Several factors favor the use of cell therapy for disc repair. The nucleus is contained by the annulus limiting cell migration, and the limited blood supply provides an immunologically privileged environment. Conversely, transplanted cells must deal with the same suboptimal conditions of limited blood supply and mechanical stresses that initially led to loss of native disc cells and decreased ECM production. Therefore, cell therapy must be instituted relatively early in the degenerative cascade prior to advanced DDD with concomitant end plate sclerosis and extensive annular degeneration.