Engineering extracellular matrix-based hydrogels for intervertebral disc regeneration

Abstract

Lower back pain (LBP) is a major health concern, especially in older adults. A key aetiological factor is intervertebral disc (IVD) degeneration. It is mediated by dysregulation of extracellular matrix (ECM) and inflammation. In recent years, regenerative therapies have garnered attention for their potential to restore disc function by addressing the underlying biological alterations within the IVD. This review focuses on the comprehensive understanding of the anatomy and physiology of the IVD, highlighting its life cycle from embryonic development, and maturation to degenerative phenotype. We describe current treatments for managing LBP caused by IVD degeneration. This review emphasizes on the recent advancements in hydrogel engineering, highlighting natural, synthetic, and composite hydrogels and their application in ECM-targeted regenerative therapy for IVD degeneration. By exploring innovations in hydrogel technology, including improvements in crosslinking techniques and controlled degradation rates-we discuss how these materials could enhance IVD regeneration and potentially be used for the management of LBP. With their enhanced biomimicry, hydrogel-based ECM mimics offer a promising pathway for developing effective, durable therapies that address the root causes of disc degeneration, providing new hope for individuals living with chronic LBP.

Keywords: biomaterials; extracellular matrix; hydrogel; intervertebral disc degeneration; lower back pain.

FIGURE 1

Schematic illustration of IVD development. (a) Early embryonic stage showing the notochord and sclerotome derived from somites. (b) Segmentation of the notochord, which will contribute to the formation of the NP within each IVD, while surrounding sclerotomal cells form the AF and vertebral bodies (VB). (c) Mature structure of the IVD, with a central NP surrounded by AF, CEP, and adjacent vertebrae. The schematic was created with BioRender.com.

FIGURE 2

Pathophysiology of IVDD. The schematic illustrates key initiating factors—such as ageing, mechanical trauma, and poor nutrition—that drive degenerative changes in the disc. These lead to reduced cell density, ECM synthesis, and hydration, along with increased inflammation, ECM degradation, vascularisation, and nerve ingrowth. Created with BioRender.com.

FIGURE 3

Schematic representation of hydrogel-based therapeutic strategies for IVD regeneration, highlighting material–cell interactions and mechanisms of action in NP and AF regions. Three main hydrogel categories—natural, synthetic, and composite—are illustrated, each offering distinct properties: natural hydrogels support biocompatibility, synthetic hydrogels enable tunable mechanics, and composites integrate both. Upon injection, the hydrogel modulates the IVD environment by reducing inflammation, promoting ECM synthesis, enhancing NP cell viability, and restoring NP-specific phenotype (↑SOX9, ↑Collagen II, ↑Aggrecan). In the AF region, the hydrogel reinforces mechanical strength, seals defects, and prevents NP herniation. These combined effects contribute to disc regeneration by restoring structure, hydration, and function. The schematic was created with BioRender.com.

FIGURE 4

(a) Chemical structure of HA, highlighting its hydrophilic groups, enzymatic cleavage sites, and possible chemical modification points. (b) synthesis of HA by synthase enzymes (HAS1, HAS2, HAS3) and its degradation via enzymatic (hyaluronidases) and non-enzymatic (ROS, hydrolysis, thermal) pathways. (c) HA’s interactions in the ECM, forming networks with proteoglycans and binding to cell surface receptors. Figure adapted from Vaudreuil et al. (2017). (d) This schematic illustrates key chemical modifications of HA, including esterification, amidation, and hydroxyl functionalization. Esterification alters hydroxyl (-OH) groups. Amidation modifies carboxyl (-COOH) groups using carbodiimide chemistry (EDC/DCC). Hydroxyl functionalization introduces reactive groups such as thiols (-SH) and esters. Additionally, crosslinking strategies improve mechanical properties and stability, making these modifications essential for hydrogel engineering and tissue regeneration. Figure adapted from (Rizvi, 2015). (e) Effects of HA-hydrogel implantation on glycosylation in the injury-induced pain model. SNA-I (red label) and GS-I-B4 (green label) binding to α-(2,6)-linked sialic acid and α-galactose, respectively. Expressions of chondroitin sulfate (purple label) and keratan sulfate (yellow label) were denoted in the sham control, untreated injury and HA-hydrogel-treated injury groups, in AF and NP tissues. Figure adaptation from Mohd Isa et al (Mohd Isa et al., 2018).

FIGURE 5

This schematic depicts the alginate crosslinking process. (a) Alginate is a polysaccharide composed of β-D-mannuronate (M) and α-L-guluronate (G) residues, with their sequence and ratio influencing gel properties. (b) The crosslinking reaction involves GDL as a proton donor and CaCO₃ as a calcium ion source, generating gluconic acid, carbon dioxide, and a calcium-alginate complex. (c) The released Ca²⁺ ions bind to alginate’s carboxyl groups, creating ionic crosslinks that form a stable hydrogel network. Figure adapted from (Gan et al., 2017). (d) In gels formulated with a 1:2 ratio of CaCO₃ to GDL, the 1× CaCO₃ concentration results in weak crosslinking and an irregular, slightly conical shape due to limited calcium release, leading to lower mechanical stability. The 2× gel demonstrates better uniformity and more complete crosslinking, while the 3× gel exhibits the highest structural integrity, though trapped air bubbles may compromise mechanical strength. In contrast, the CaCl₂-crosslinked gel undergoes rapid shrinkage and shows poor geometry due to the oversaturation of calcium, resulting in uneven crosslinking and mechanical instability. Figure adapted from (Growney Kalaf et al., 2016).

FIGURE 6

(a) Schematic representation of collagen crosslinking. Collagen’s reactive groups (-NH₂ and -COOH) combine with different chemical crosslinkers to create a stable collagen hydrogel. The main crosslinkers shown include glutaraldehyde, genipin, carbodiimide, PEGDA, and PPU, each influencing mechanical properties and biocompatibility. Figure adapted from (Li et al., 2021). (b) Laser scanning microscopy images showing adipose stem cells within the collagen hydrogel. (a) After 2 h, cells have spread, and after 36 h, cytoskeletons are formed (red) and nuclei are visible (blue), demonstrating cell vitality. Scale bar: 50 µm. Adapted from Friedmann et al. (Wang et al., 2024b). (c) Histological sections of intervertebral discs treated with collagen hydrogel loaded with adipose stem cells. Native, untreated disc section showing intact NP structure (A) Damaged disc section post-injury with notable NP degeneration (white arrow indicating damaged region) (B) Collagen hydrogel-treated disc showing partial restoration of NP structure (C) Adapted from Friedmann et al. (Friedmann et al., 2021).

FIGURE 7

Schematic representation of ECM analogue-conjugated PEG-based hydrogel formation. Vinyl sulfone (VS)-functionalized PEG is crosslinked using MMP-sensitive peptides, allowing controlled degradation in response to enzymatic activity. This strategy enhances bioactivity by enabling cell adhesion through conjugated peptides or recombinant proteins. Figure adapted from (Lim et al., 2013).