On the Horizon From the ORS

Biologic Repair and Regeneration of the Intervertebral Disk Low back pain (LBP) is a common clinical problem with great socioeconomic impact on the aging population. Because of the lack of precise knowledge regarding the pathogenesis of intervertebral disk (IVD) degeneration, the current diagnosis of discogenic LBP is uncertain, and current methods of managing discogenic LBP are not scientific or evidence based. Many nonsurgical and surgical treatments of LBP are ineffective, a fact that further increases the costs of health care as well as the number of patients with chronic LBP and failed back syndrome. Better understanding of the biologic mechanisms associated with IVD degeneration and discogenic LBP will likely lead to the discovery of biomarkers that may help diagnose discogenic LBP more accurately and thereby lead to more biologic and mechanistic management strategies. Although the IVD is a major load-bearing structure in the spine, the exact relationship between IVD degeneration and LBP has not been established. The overall goal of our research has been to better understand IVD biology and the pathophysiology of IVD degeneration so that patients with discogenic LBP may be afforded more effective diagnosis and management options. For more than a decade, we have focused our research on discovering and characterizing important molecules associated with IVD degeneration as well as on testing potential compounds to manage IVD degeneration. Examining IVD tissue donated from patients who have undergone back surgery as well as from cadavers has enabled us to study the biologic mechanisms of LBP and IVD degeneration. We have shown that the content of large proteoglycans (PGs), such as aggrecan and versican, decreases with aging and IVD degeneration, whereas the content of certain small PGs, such as biglycan, increases with aging and IVD degeneration.1 Proinflammatory cytokines, such as interleukin-1 and tumor necrosis factor-α, are also associated with IVD degeneration. These molecules could be potential biomarkers of IVD degeneration and, thus, targeted for therapy. Our research group has developed in vitro IVD cell and organ culture models and in vivo animal models to study IVD degeneration and repair.2 Using these models, candidate therapeutic agents have been tested to assess their therapeutic potential for matrix restoration. Using our rabbit annular puncture model of IVD degeneration, injections of either bone morphogenetic protein (BMP)-7 (also known as osteogenic protein-1 [OP-1]; Stryker, Kalamazoo, MI)3 or BMP-14 (also known as growth and differentiation factor-5 [GDF-5]),4 were shown to be effective in restoring IVD height, MRI signals of the IVD, biochemical matrix contents, and disk biomechanical properties. Based on these preclinical data, the US FDA has recently allowed initiation of Investigational New Drug clinical trials on OP-1 and GDF-5 in the United States. Understanding the molecular mechanisms of LBP continues to be challenging because of the diversity of patients. As we have uncovered the complications of disk degeneration and pain, we have come to realize that future biologic therapies will need to be personalized. Protein therapies (eg, OP-1, GDF-5) may be safe and effective in treating early-stage IVD degeneration when injected directly into the IVD. However, protein treatments may have limitations because they are unable to make a notable impact in intermediate to advanced stages of degeneration. In IVDs with higher grades of degeneration, the number of cells responsive to growth factor stimulation diminishes. In this setting, cell therapy or cell-based gene therapy may be useful management strategies, by which transplanted cells can repopulate the IVD and deliver growth signals. At the most advanced stage of degeneration, a tissue-engineering approach may be necessary to restore IVD function. Our ongoing work is to continue to test other biologic therapies, anti-inflammatory proteins, cell therapy, and cell-based gene therapy,5 which may reverse IVD degeneration and reduce LBP. We also intend to discover and target pain-mediated molecules associated with IVD degeneration. Our future studies include the development of in vitro and in vivo models that will be used to determine whether candidate molecules not only upregulate matrix molecules but also reduce LBP. Our studies have helped lay the groundwork for clinicians and scientists worldwide to understand the molecular mechanisms of disk degeneration and to design and test biologic treatments against disk diseases. Because of this work as well as continuing knowledge, we hope to provide clinicians with a variety of treatment options that would be personalized for each patient and that would fully restore spinal structure and function and relieve LBP. Howard S. An MD Koichi Masuda MD, PhD Gabriella Cs-Szabo PhD Yejia Zhang MD, PhD Ana Chee PhD Gunnar B. J. Andersson MD, PhD Hee-Jeong Im PhD Eugene J.-M.A. Thonar PhD An Evidence-based Approach in Understanding “Pseudotumors” in Metal-on-metal Hip Replacements Metal-on-metal hip resurfacing arthroplasty (MoMHRA) has undergone a recent resurgence as an alternative treatment option for young, active patients with considerable hip osteoarthritis. Despite satisfactory short-term implant survivorship, abnormal periprosthetic soft-tissue masses relating to the hip joint (ie, pseudotumors) increasingly are being reported.6 These masses were found to be locally destructive, requiring revision surgery in a high proportion of patients (75%), the outcome of which is poor.7 However, no definitive evidence exists of potential mechanisms involved in the occurrence of such destructive soft-tissue masses. Studies were undertaken to determine the extent of this emerging clinical complication (ie, pseudotumor) with a high revision burden and to determine whether pseudotumor arises from a local biologic reaction to an increased wear-debris burden generated by excessive MoMHRA implant wear. A clinical study investigated the prevalence of, and association between, pseudotumors and serum metal ion levels in 158 patients (201 hips) with MoMHRA.8 The overall prevalence of asymptomatic pseudotumor was found to be 4%, considerably higher than had been previously reported. The study also established that pseudotumor occurred only with elevated metal ion levels, suggesting that the underlying cause is increased wear. The authors postulated that pseudotumors are likely to be a biologic reaction to the large amount of metal debris generated in vivo because of excessive wear. Two potential biologic reactions mediating the occurrence of pseudotumors were then investigated. An in vitro clinical study demonstrated that systemic hypersensitivity type IV reaction, mediated by lymphocyte reactivity to these metals, is not the dominant biologic response involved in pseudotumors.9 Lymphocytic infiltration was not seen histologically in all pseudotumors, whereas necrosis and a macrophage infiltrate were always observed. A further in vitro experiment demonstrated that nanometer-sized metal particle-induced cytotoxicity is likely to be an important factor leading to pseudotumors.10 Subsequent research focused, first, on assessing the magnitude of bearing surface wear that occurs in pseudotumor patients and, second, on elucidating the potential wear mechanism responsible for the increased implant wear in these patients. A retrieval study demonstrated that MoMHRA implants revised because of pseudotumor were associated with statistically significantly greater linear wear rates.11 This fact, combined with the metal ion data, confirmed that pseudotumor is associated with increased wear at the MoM articulation. An edge-loading wear pattern was consistently found in the pseudotumor group. An in vivo study was then developed to investigate whether the edge-loading occurs during functional activities. Edge-loading in the pseudotumor group was found to occur with up to a fourfold increase in duration and up to a sevenfold increase in force. This in vivo finding supported the in vitro retrieval study finding of an edge-loading wear pattern in the pseudotumor group, suggesting that edge-loading during functional activities is an important in vivo mechanism responsible for localized high wear and subsequent elevation of metal ion levels in MoMHRA patients with pseudotumors. Pseudotumor is likely to result from a local biologic reaction to increased metal debris load, generated by excessive MoMHRA implant wear caused by edge-loading. In susceptible patients, the dose-dependent cytotoxicity of wear debris leads to subsequent necrosis of periprosthetic soft tissues. Clinicians need to be aware of pseudotumors, and surgeons should undertake MoMHRA with great care because, even with satisfactory component positioning, the problem can occur. In evaluating MoMHRA patients with unexplained symptoms and with normal plain radiographs, further investigation with cross-sectional soft-tissue imaging modalities (eg, ultrasonography, MRI) is recommended. Young-Min Kwon MD, PhD, FRCS, FRACS