Development Of A Composite Tissue-Engineered Intervertebral Disc: In Vitro And In Vivo Structure And Function

摘要

Degenerative disc disease and its associated spinal disorders are a leading cause of disability in the United States and around the world. Currently a number of treatments exist, but they are mostly palliative in nature and fail to restore function to the spine. The field of tissue engineering provides the opportunity to create treatments that will replace the diseased tissue with new tissue and that can not only relieve the symptoms of the patient, but can also restore function. This dissertation focuses on the development of a composite tissue-engineered intervertebral disc (TE-IVD) that can be used to replace the diseased intervertebral disc (IVD) in the spine. TE-IVDs were developed with circumferentially aligned collagen fibrils and cells in the annulus fibrosus (AF) region of the IVD by contracting cell-seeded collagen gels around a cell-seeded alginate gel nucleus pulposus (NP). Altering the original collagen concentration and cell seeding density was able to regulate the final AF composition and collagen alignment in the TE-IVD. Using the tunable AF region of the TE-IVD, the effects of altering the AF composition and architecture on TE-IVD tissue development were studied both in vitro and in the native disc space. It was determined that changes in the AF composition led to altered pressurization of the TEIVD under load and this change in mechanics regulated the in vivo tissue development. These in vivo studies were the first to demonstrate that tissue- engineered total disc replacement (TE-TDR) could produce an integrated and mechanically functional IVD-like tissue in the native disc space. Despite the enthusiasm for TE-TDR, this is the first body of work that demonstrated a TE-IVD could replace and restore function to the spine when implanted into the disc space. Furthermore, the field has largely focused on the collagen organization of the AF in TE-IVD design, but this dissertation presents AF hydraulic permeability as a key design parameter due to its ability to regulate proper tissue development in the native disc space. Overall, this work represents a benchmark in TE-IVD research and pushes TE-TDR towards the clinic.