Cellular And Mechano-Active Material Approaches To Improve Disc Repair After Herniation

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Doctor of Philosophy (PhD)
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disc herniation
drug delivery
intervertebral disc
regenerative medicine
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Peredo Nery, Ana Paula

The intervertebral disc (IVD) relies on its complex microarchitecture and composition to transmit forces throughout the spine. A nucleus pulposus (NP) core is surrounded circumferentially by the annulus fibrosus (AF), which together transmit loads to adjacent vertebra. Although this specialized structure evolved over millennia, the disc failed to develop mechanisms for self-repair. Instead, cell apoptosis and inflammation after injury lead to the loss of extracellular matrix and further compromise disc function. Furthermore, adult disc cells are sparse and have decreased biosynthetic abilities. Disc herniations, resulting from annular tears, enable the extrusion of NP tissue which can result in spinal nerve compression and consequent pain. The gold standard for the surgical management of symptomatic disc herniation is microdiscectomy, in which the herniated tissue is removed. This alleviates pain yet fails to repair the injured disc, leaving an uninhibited track for recurrent herniation. This highlights the need for the development of disc repair strategies that improve healing and prevent recurrent herniation. To that end, the main objectives of this work were to develop cellular, molecular, and structural augmentation strategies for the repair of disc herniations. For cellular augmentation, an AF-like cell population was developed through differentiation of human induced pluripotent stem cells (iPSCs). Factors present during disc development were screened and their inductive effects were assessed through transcriptional signature comparisons between iPSC-derived AF-like cells and mature AF cells. To enable molecular augmentation of the injury, a drug delivery system termed mechanically-activated microcapsules (MAMCs) was developed. MAMC properties, including mechano-activation and degradation, were investigated to characterize the tunability of the system. Finally, structural augmentation of the injured disc was achieved through the development of tension-activated repair patches (TARPs), which deliver factors through the activation of encapsulated MAMCs. TARP-mediated disc repair and provision of anti-inflammatory factors was analyzed in a large animal model. The provision of structural support and anti-inflammatory molecules improved the retention of disc composition and improved repair. These annular augmentation strategies hold promise for continued preclinical development and future translation into humans.

Robert L. Mauck
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