The intervertebral disc (IVD) is a fibrocartilaginous tissue situated between vertebral bodies along the spinal column and facilitates controlled flexibility and stability of the spine. Back pain is the leading cause of disability worldwide and is commonly associated with IVD pathologies such as herniation and degeneration. Defects in the annulus fibrosus (AF) can arise from IVD injury and/or degeneration and may lead to debilitating and painful symptoms that warrant surgical intervention. Surgical treatment strategies such as discectomy can operatively rectify pain associated with herniation but does not repair the AF and can lead to postoperative complications as well as recurrent pain in a clinically significant population. Recurrent herniation and progressive degeneration are two prominent postoperative complications that highlight the unmet need to develop minimally invasive treatment strategies that can repair the AF so as to diminish incidence of recurrent herniation and degeneration following surgery. Tissue engineering and regenerative medicine has emerged as a promising field to develop the next generation of surgical treatment strategies by utilizing a combination of biomaterial scaffolds, bioactive factors, and/or cells to promote biomechanical and biological AF repair.

The global objective of this thesis was to develop an injectable hydrogel system with pro-regenerative properties that can:​ (1) durably bond to AF tissue so as to prevent recurrent herniation, and (2) enhance the AF’s endogenous repair capacity by ameliorating hallmarks of degeneration. To engineer a bioadhesive hydrogel system, polymeric biomaterials must interact on a molecular basis with biomolecules in the extracellular matrix. The two-part biomaterial system developed in this thesis employs methacrylated and oxidized glycosaminoglycans as an injectable tissue coating to form tunable covalent bonds between a void-filling interpenetrating network hydrogel and extracellular matrix proteins in the AF. This work systematically optimized hydrogel-tissue adhesion strength by means of biochemical modifications and glycosaminoglycan subtype. Results indicated that dual-modified hyaluronic acid underwent higher extents of conversion and imparted greater adhesion strength than dual-modified chondroitin sulfate. After identifying the optimal methacrylated and oxidized glycosaminoglycan product, this two-part biomaterial platform was scaled up to a large animal model of discectomy ex vivo and the effect of hydrogel mesh size on IVD herniation risk was determined. Findings showed that low-modulus hydrogels with a large mesh size were mechanically compliant and minimized herniation risk equivalent to that of the current standard of care. This platform was further developed to incorporate PLGA microspheres for the delivery of mesenchymal stem cell (MSC)-derived exosomes to promote biologically active AF repair. Results showed that AF cell treatment with MSC-exosomes led to increased migration, enhanced proliferation, and gene expression levels were comparable to healthy controls, demonstrating their therapeutic promise as a stem cell-free approach for regenerative AF repair. Notably, cellular treatment responses were sensitive to biological donor and culture environment of the exosome source cells. PLGA microspheres demonstrated proof-of-concept exosome encapsulation and release, while not deleteriously affecting the environmental pH or mechanical properties of hydrogel constructs upon carrier embedment or degradation. Overall, this work advanced the development of exosome-laden adhesive hydrogels for bioactive AF repair.