Tissue Engineering Strategies for Total Disc Replacement: Structure and Mechanical Function of the Intervertebral Disc

Degenerative disc disease (DDD) is implicated as one of the primary causes of lower back pain (LBP), the leading cause of disability worldwide. This degeneration is characterized by irreversible detrimental changes to the structure of the intervertebral disc (IVD) which then severely impairs its mechanical function in the spine. The gellike nucleus pulposus (NP) at its core loses its ability to hydrate while damage propagates through the surrounding annulus fibrosus (AF) in the form of tears and lesions, rendering it unable to resist elastic deformation. Current surgical interventions treat the painful symptoms of the disease rather than the underlying causes, providing only a temporary solution. Tissue-engineered (TE) repair strategies have been proposed for the last two decades as a means of preventing disease advancement in the long term, aiming to restore the native disc’s structure as well as repair damage to the cell population. While promising, recapitulating the disc’s complex fibrous architecture and mechanical behavior represents an enduring challenge in the field, particularly in attempts to scale up to larger animal models for clinical translation.

This thesis sought to augment engineered constructs in vitro by investigating the interplay between matrix composition and mechanical behavior, as well as provide mechanical support to constructs for in vivo delivery. In particular, it describes how the manipulation of fiber formation through media glucose content in vitro plays a critical role in governing matrix structure and mechanical integrity (Chapter 1); how these same mechanisms function in a diseased state in vivo to influence the developing disc (Chapter 2); and how providing a supplemental cage structure to immature TE-IVDs can prevent initial displacement and collapse following implantation to eventually ensure successful tissue integration. Collectively, the work presented here offers crucial insight into how to continue the advancement of biologically based TDR strategies towards use in the clinic.

Year	Entry
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Year

Entry

2002

Smit TH. The use of a quadruped as an in vivo model for the study of the spine: biomechanical considerations. Eur Spine J. April 2002;11(2):137-144.

2002

Davisson T, Kunig S, Chen A, Sah R, Ratcliffe A. Static and dynamic compression modulate matrix metabolism in tissue engineered cartilage. J Orthop Res. July 2002;20(4):842-848.

2007

Tang SY, Zeenath U, Vashishth D. Effects of non-enzymatic glycation on cancellous bone fragility. Bone. April 2007;40(4):1144-1151.

1975

Maroudas A, Stockwell RA, Nachemson A, Urban J. Factors involved in the nutrition of the human lumbar intervertebral disc: cellularity and diffusion of glucose in vitro. J Anat. September 1975;120(1):113-130.

1995

Buschmann MD, Gluzband YA, Grodzinsky AJ, Hunziker EB. Mechanical compression modulates matrix biosynthesis in chondrocyte/agarose culture. J Cell Sci. April 1995;108(4):1497-1508.