Putting the Pieces in Place: Mobilizing Cellular Players to Improve Annulus Fibrosus Repair

Abstract

The intervertebral disc (IVD) is an integral load-bearing tissue that derives its function from its composite structure and extracellular matrix composition. IVD herniations involve the failure of the annulus fibrosus (AF) and the extrusion of the nucleus pulposus beyond the disc boundary. Disc herniations can impinge the neural elements and cause debilitating pain and loss of function, posing a significant burden on individual patients and society as a whole. Patients with persistent symptoms may require surgery; however, surgical intervention fails to repair the ruptured AF and is associated with the risk for reherniation and further disc degeneration. Given the limitations of AF endogenous repair, many attempts have been made toward the development of effective repair approaches that reestablish IVD function. These methods, however, fail to recapitulate the composition and organization of the native AF, ultimately resulting in inferior tissue mechanics and function over time and high rates of reherniation. Harnessing the cellular function of cells (endogenous or exogenous) at the repair site through the provision of cell-instructive cues could enhance AF tissue regeneration and, ultimately, improve healing outcomes. In this study, we review the diverse approaches that have been developed for AF repair and emphasize the potential for mobilizing the appropriate cellular players at the site of injury to improve AF healing. Impact statement Conventional treatments for intervertebral disc herniation fail to repair the annulus fibrosus (AF), increasing the risk for recurrent herniation. The lack of repair devices in the market has spurred the development of regenerative approaches, yet most of these rely on a scarce endogenous cell population to repair large injuries, resulting in inadequate regeneration. This review identifies current and developing strategies for AF repair and highlights the potential for harnessing cellular function to improve AF regeneration. Ideal cell sources, differentiation strategies, and delivery methods are discussed to guide the design of repair systems that leverage specialized cells to achieve superior outcomes.

Keywords: annulus fibrosus; biomaterials; cell delivery; cellular function; intervertebral disc herniation; regeneration.

FIG. 1.

Acellular biomaterial-based approaches for AF repair. AF repair strategies in development employ hydrogel sealants or scaffolds to seal AF lesions and prevent further loss of NP tissue to ultimately reestablish the tissue’s mechanical function and prevent recurrent IVD herniation. AF, annulus fibrosus; IVD, intervertebral disc; NP, nucleus pulposus.

FIG. 2.

Acellular AF repair strategies. (a) Representative Alcian Blue histological staining of ovine specimens through the defect location 6 weeks after surgery for unrepaired and combined repair groups, with HDC repair of the AF and NP replacement with HA (scale bar: 5 mm). Figure was republished with permission from Science Translational Medicine. (b) Representative Safranin O–Fast Green histological staining of ovine specimens 12 months after surgery for unrepaired and FibGen repair groups, with highlighted disrupted AF lamella (arrow) and blood vessel ingrowth (red circle) in both groups (scale bar: 2 mm). Figure was republished with permission from JOR Spine. (c) Representative Hematoxylin/Eosin/Safran (HES) histological staining of ovine specimens 4 weeks after surgery for unrepaired and polycaprolactone nanofibrous scaffold repair groups, highlighting the implanted multilayer scaffold (arrows), the patch used to secure the scaffold in place (#), and vascular ingrowth (circle) (scale bar: 5 mm for full disc sections and 1 mm for high magnification images). Top left insets show MRI images of discs. Figure was republished with permission from Biomaterials. HDC, high-density collagen; FibGen, fibrin-genipin; HA, hyaluronic acid.

FIG. 3.

Recruitment of endogenous AF cells to the site of injury to enhance repair. The low cell density of the native AF is detrimental for endogenous tissue repair. Biomaterial-based repair systems, such as hydrogels with molecule-eluting fibers, can be engineered to release chemoattractants that increase cellular chemotaxis toward the site of repair. Native AF cells can then reestablish the lost tissue matrix and organization, effectively repairing AF lesions and preventing IVD reherniation.

FIG. 4.

Delivery of exogenous cells to repair AF injuries. Due to the characteristic dense extracellular matrix of the native AF, endogenous cells may have difficultly migrating to the site of repair. To circumvent this issue, biomaterial-based repair systems can be employed to deliver exogenous cells to the AF injury, enabling the localized provision of specialized cells and the presentation of cell-guidance cues, such as growth factors, to direct the behavior and phenotype of implanted cells.

FIG. 5.

Exogenous cell delivery repair strategies. (a) Representative Alcian Blue histological staining of ovine specimens 6 weeks after surgery for unrepaired and MSC-seeded HDC repair groups, highlighting NP extrusion in the unrepaired group (†) and a buttress (star) preventing NP herniation in the cell delivery group (scale bar: 0.5 mm). Figure was republished with permission from Neurosurgery. (b) Representative Safranin O–Fast Green histological staining of mice specimens 8 weeks after surgery for AF injuries treated with MSC- or Mkx-overexpressing MSC-seeded collagen solution, injected through the left side of the images (scale bar: 300 μm). Figure was republished with permission from Nature Communications. (c) Representative Hematoxylin and Eosin histological staining of ovine specimens 6 months after surgery of unrepaired and repaired groups that received MSCs primed with pentosan polysulfate implanted in a gelatin sponge. Arrows highlight vascular proliferation in the unrepaired group and the lamellar structure in the primed MSC delivery group (scale bar: 1 mm). Figure was republished with permission from The Spine Journal. Mkx, Mohawk; MSC, mesenchymal stromal cells.