Between 2001 and 2010, more than 130,000 active service members received diagnoses of intervertebral disc (IVD) degeneration, with annual incidence rates more than doubling over this period. Over 68,000 days of lost duty time were attributed to disc degeneration-specific diagnoses. Military training and operations are inherently physically demanding, placing military service members at increased risk for IVD degeneration and related neck and back pain. Among Veterans, chronic back pain accounts for over 70 percent of chiropractic visits and in many cases is directly connected to their period of service. Despite the prevalence and soaring costs, there is no specific treatment that restores physiological functions of the diseased IVD. The objective of this pilot study is to confirm that young allogeneic articular chondrocytes, especially those induced to overexpress growth factors (e.g., bone morphogenetic protein, BMP-7) are effective in repairing the degenerating IVD. Articular chondrocytes would be an appropriate cell source because they already have a phenotype similar to that of the IVD cells, and, unlike native disc cells, have greater potential for clinical translation through allogeneic transplantation. Young chondrocytes will be used here because a body of literature supports the notion that young cells possess more regenerative capacity than older cells by rejuvenating host tissue via trophic factors. Our team has pioneered the development of a rabbit IVD-injury model which is ideally suited to evaluating cell-based therapeutics. Our preliminary data have shown that young allogeneic articular chondrocytes injected into the center of the injured rabbit IVD survived and reduced inflammation of the host tissue. In the proposed study, hydrogels with distinct properties will be assessed as scaffold that may prevent leakage from the injection needle track and enhance biomechanical properties of the repaired IVD. The injectable implants shown to mimic the native NP in mechanics will be more likely to induce the appropriate phenotype in the cells as the disc is loaded in vivo. Specifically, our group has developed hyaluronic acid (HA)-based hydrogels conducive to preservation of chondrocyte phenotype and growth, which solidify at body temperature and are thus ideal for injection therapies. We have also tested a triple-interpenetrating-network (TIN) hydrogel that enhances biomechanical properties of the repaired IVD. Based on our preliminary studies, we hypothesize that transplanting articular chondrocytes seeded in hydrogels will repopulate the IVD thus reducing inflammation and enhancing biomechanical properties by providing trophic factors and synthesizing extracellular matrix.
Two specific aims are proposed, to test this hypothesis.
In Aim 1, we will compare the HA and TIN gel in supporting transplanted articular chondrocyte survival and reducing host inflammatory responses in the rabbit IVD-injury model. The hydrogel that best supports cell survival and reduces host inflammation will be further tested.
In Aim 2, we will determine the therapeutic effects of young articular chondrocytes on injured mature rabbit IVDs. The effects of chondrocytes (native or overexpressing bone morphogenetic protein (BMP)-7) on the host IVD inflammation, biomechanical properties, and tissue structure will be determined. We expect that IVDs repaired with chondrocytes seeded in hydrogel will show improved biomechanical properties, decreased inflammation, and improved morphology. These studies in the rabbit will lay the groundwork for clinical studies that will test if transplanted chondrocytes are effective in reducing disc degeneration and back pain, thus benefiting patients.
More than 130,000 active service members received diagnoses of intervertebral disc (IVD) degeneration between 2001 and 2010, with annual incidence rates more than doubling over this period. Among Veterans, chronic back pain accounts for over 70 percent of chiropractic visits and in many cases is directly connected to their period of service. We expect that IVDs repaired with chondrocytes seeded in hydrogel will show improved biomechanical properties, decreased inflammation, and improved structure. These studies in the rabbit will lay the groundwork for clinical studies that will test if transplanted chondrocytes are effective in reducing disc degeneration and back pain, thus benefiting patients.
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