Critical aspects and challenges for intervertebral disc repair and regeneration-Harnessing advances in tissue engineering

Abstract

Low back pain represents the highest burden of musculoskeletal diseases worldwide and intervertebral disc degeneration is frequently associated with this painful condition. Even though it remains challenging to clearly recognize generators of discogenic pain, tissue regeneration has been accepted as an effective treatment option with significant potential. Tissue engineering and regenerative medicine offer a plethora of exploratory pathways for functional repair or prevention of tissue breakdown. However, the intervertebral disc has extraordinary biological and mechanical demands that must be met to assure sustained success. This concise perspective review highlights the role of the disc microenvironment, mechanical and clinical design considerations, function vs mimicry in biomaterial-based and cell engineering strategies, and potential constraints for clinical translation of regenerative therapies for the intervertebral disc.

Keywords: biomaterials; clinical translation; mechanical compatibility; microenvironment; mimicry; tissue engineering.

Figure 1

Variations in intervertebral disc (IVD) structure and composition with aging vs degeneration. Picrosirius red/alcian blue (PR/AB) staining of mid‐sagittal sections of four different human IVDs. PR/AB highlights the differences between IVD aging and IVD degeneration. Column 1. Aging: Aging IVDs show subtle changes in structure and composition with retention of overall annulus fibrosus (AF) structural integrity. (A) Forty‐four‐year‐old male IVD retains healthy end plates with only slight irregularities, well‐organized annular morphology, nearly normal nuclear tissue with only slight disorganization, and intense matrix staining. (B) Eighty‐one‐year‐old female IVD shows only slight irregularities in the endplate. It maintains a well‐organized annulus with only slight loss of annular‐nuclear demarcation, and mild loss of nuclear staining intensity. This aged specimen also shows rounded end plates due to osteoporotic changes in underlying trabecular bone. Column 2. Degeneration: Degenerated IVDs show larger changes in structure that disrupt the gross integrity of the AF, the nucleus pulposus, and/or the end plates and changes in composition with loss of staining intensity. (C) Forty‐seven‐year‐old female exhibits multiple irregularities in the endplate including thinning and focal breaks, a loss of boundary demarcation between the nucleus and annulus, and disorganized/fibrotic nuclear matrix and little AB staining. The IVD also displays horizontal fissures that extend into the annulus and disrupt its structure. (D) Eighty‐five‐year‐old male IVD shows severe irregularities in the endplate, disorganization of the nucleus and complete rupture of the annulus. The faint staining shows nearly complete loss of matrix material, leading to collapse of the disc, bulging of the annulus, and areas of bone to bone contact. In this extreme case, there is complete loss of structural integrity of the IVD

Figure 2

Summary of physicochemical microenvironmental factors and key questions for successful clinical translation. Integrating biomedical imaging strategies with biomarker screening are key aspects to help identify and stratify suitable patient cohorts for cell‐based regeneration

Figure 3

Testing paradigm for evaluating intervertebral disc (IVD) repair strategies. Screening tests involve high throughput evaluations that can rapidly assess materials. Testing process progresses to in vivo validation. This figure was modified from Long et al51

Figure 4

In situ biomechanical testing for advanced screening can include six degrees of freedom testing to evaluate spine biomechanical properties. These biomechanical properties can characterize the neutral zone as well as the stiffness and hysteresis. In situ biomechanical validation tests can also include acute and fatigue failure simulation

Figure 5

Nucleus pulposus (NP) mimics may consist of natural or synthetic hydrogels, decellularized matrix, specific adhesion proteins or osmo‐responsive molecules; while annulus fibrosus (AF) mimics may be realized with crosslinked hydrogels or fibers arranged in oriented angle‐ply laminates. Challenges in reproducing the authentic tissue include: interfaces NP‐AF‐cartilaginous endplate (CEP)‐vertebrae; integration with native structures; degradation and remodeling properties; regulation of osmotic pressure; complexity of natural matrix, glyco‐pattern, small molecules; cell adhesion properties; cell phenotype regulation; in vitro‐ex vivo‐in vivo translation. Potential strategies for implant integration are displayed