Application and prospects of polysaccharide-based hydrogels in the treatment of intervertebral disc degeneration

Abstract

Intervertebral disc degeneration (IVDD) is a primary contributor to chronic low back pain (LBP) and neurological dysfunction. It significantly impairs patients' quality of life. With an aging population and changing lifestyles, the incidence of IVDD has been rising steadily. However, traditional treatments, such as medications, physical therapy, and surgery, primarily alleviate symptoms without fundamentally repairing degenerated discs. Recent advances in tissue engineering and regenerative medicine have led to the development of new therapeutic strategies for IVDD. Among them, hydrogels, which are materials with excellent biocompatibility and tunable properties, show remarkable potential. In particular, polysaccharide-based hydrogels offer unique advantages in IVDD repair thanks to their structural and functional resemblance to native tissues. Their inherent biomimetic properties allow precise replication of the extracellular matrix (ECM) microenvironment in intervertebral discs, providing critical biochemical and biomechanical cues for cell adhesion, proliferation, and differentiation. Additionally, polysaccharide-based hydrogels, with their diverse material bases and modification methods, can flexibly meet the specific demands of various polysaccharide types, providing highly customizable solutions for different stages of the repair process. This paper presents a comprehensive review of recent developments in the application of polysaccharide hydrogels for IVDD therapy.

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1. Introduction

Low back pain (LBP) is the leading cause of disability worldwide and represents a major global public health challenge.¹ Epidemiological data from 2020 indicates approximately 619 million people were affected worldwide, with projections suggesting this number will rise to 843 million (759–933 million) by 2050.² Intervertebral disc degeneration (IVDD) is a primary contributor to chronic back pain and functional loss, and its incidence increases significantly with age. LBP and dysfunction caused by IVDD not only affect patients’ quality of life but also impose an enormous social and economic burden.^3,4

At present, commonly used treatments for IVDD include pharmacological therapy, physical therapy, and surgical interventions (Fig. 1).³ Pharmacological therapy mainly includes non-steroidal anti-inflammatory drugs and analgesics. Although they can relieve symptoms, they do not repair degenerated intervertebral discs and may cause gastrointestinal, cardiovascular, and renal side effects with long-term use.⁵ Physical therapy, such as traction, massage, and exercise therapy, offers limited efficacy for severely degenerated discs and is prone to relapse.⁶ Surgical interventions, including discectomy and spinal fusion, can relieve symptoms, but are related to many limitations, such as significant trauma, slow recovery, complications, and an inability to restore the disc's normal function.^4,6,7 Great progress has been made in regenerative medicine, including nerve regeneration.^8–10 In recent years, innovations in materials science and regenerative medicine have brought increasing attention to hydrogel materials due to their minimally invasive drug delivery, excellent biocompatibility, and diverse therapeutic mechanisms.^11,12

Fig. 1 Overview of various treatments for IVDD, including pharmacological therapy, general physical therapy, surgical interventions and hydrogel-based therapies, as well as the basic structure of the spine. While anti-inflammatory drugs offer temporary pain relief and physical therapy delays IVDD progression under strict supervision, polysaccharide-based biomaterials enable multifunctional intervention: mitigating inflammation, halting cellular apoptosis, and restoring biomechanical stability, which potentially avoids the need for surgical intervention. (Created with BioRender).

Polysaccharide-based hydrogels are three-dimensional network structures formed through physical or chemical crosslinking of hydrophilic polymers. They can absorb and retain large amounts of water, and usually exhibit excellent biocompatibility and biodegradability.¹³ These materials are well-tolerated by human tissues, seldom cause immune rejection, and can gradually degrade in vivo. Therefore, there is space for new tissue formation.¹⁴ Since the early pathological changes of IVDD are mainly concentrated in the nucleus pulposus (NP), this area has become an important target for new therapeutic interventions.^15–17 For instance, in clinical practice, expandable biomaterials can be used to replace dehydrated NP when the annulus fibrosus (AF) and endplate structures remain intact.¹⁸ In such cases, injectability becomes a key consideration, as hydrogel must be accurately delivered into the intervertebral disc in a minimally invasive way. This not only minimizes damage to the AF, but also effectively fills irregular defects in the NP.^19,20 Polysaccharide-based hydrogels also exhibit excellent mechanical properties, which can be adjusted by altering the degree of crosslinking and material composition to meet the mechanical needs of the intervertebral disc.^3,4 These hydrogels offer significant advantages in the treatment of IVDD: (a) polysaccharide-based hydrogels can simulate the mechanical properties of natural NP tissue, restore disc height and elasticity, and relieve spinal loading;^21,22 (b) they serve as carriers for NP cells or stem cells, which can be encapsulated and transplanted into degenerated discs to promote extracellular matrix (ECM) synthesis and tissue repair. Alternatively, growth factors such as TGF-β and BMP-2 can be loaded into controlled-release systems to continuously promote cell proliferation and differentiation;^23–26 (c) they can be implanted by injection, with minor trauma and quick recovery. Therefore, they are suitable for early intervention. These hydrogels can integrate multiple functions, such as drug release, anti-inflammatory, and mechanical repair, to realize personalized treatment.^27–29 In addition, many natural polymer hydrogels, such as chitosan and cellulose, have inherent antibacterial properties.^30–33

2. Intervertebral disc degeneration

2.1. Structure of the intervertebral disc

The intervertebral disc is an important part of the spine, located between adjacent vertebral bodies. It plays a role in shock absorption, load support, and the maintenance of spinal flexibility.³⁴ It consists of three main components: the gelatinous NP at its core, the AF surrounding it, and the cartilage endplates (CEP) positioned superiorly and inferiorly to contain the disc.³⁵ The NP, located at the center of the disc, is a gelatinous substance mainly composed of water, proteoglycans (such as aggrecan), and type II collagen fibers.³⁶ Its special structures make it possible to absorb and disperse axial loads borne by the spine. The consequent internal osmotic pressure helps maintain the disc's height and the physiological curvature of the spine.³⁷ Surrounding the NP, the AF consists of concentric lamellae of collagen fibers (mainly type I collagen) and elastic fibers. The alternating orientation of these fibers enhances the AF's mechanical strength and provides structural stability for the disc. This enables it to resist torsional and shear stresses.³⁸ The strong structure of the AF also prevents the NP from herniating under pressure.³⁹ The CEPs, located between the intervertebral disc and adjacent vertebral bodies, are thin, transparent layers of cartilage tissue mainly composed of type II collagen and proteoglycan. They act as the primary channel for nutrient delivery and waste removal between the disc and vertebral body. As such, they provide oxygen and nutrients to the avascular disc through diffusion.⁴⁰

The intervertebral disc is the largest avascular tissue in the human body, and its nutrient supply mainly depends on CEP, which greatly limits its repair capacity.⁴¹ The structure and function of the lumbar intervertebral disc are closely related. Its unique composition and mechanical properties are essential for spinal function and movement.⁴² A clear insight into the anatomical and physiological characteristics of the lumbar intervertebral disc is critical to the development of effective treatment strategies.

2.2. Pathological changes of intervertebral disc degeneration

IVDD is a complex pathological process, involving the interaction among cells, ECM, and the mechanical environment (Fig. 2).⁴³ The main pathological changes include the following aspects: (a) ECM degradation: during degeneration, the levels of proteoglycan and collagen in the NP decrease significantly. This leads to a loss of water content and elasticity in the intervertebral disc;⁴⁴ (b) apoptosis and aging: the number and functional activity of NP cells decrease, which further accelerates ECM destruction;⁴⁵ (c) inflammatory reaction: degenerated intervertebral discs release various inflammatory factors (such as IL-1β and TNF-α), which leads to pain and nerve root compression;⁴⁶ and (d) destruction of physiological structure: the disc height decreases, and its mechanical properties are reduced, eventually leading to spinal instability and nerve compression.³⁴

Fig. 2 The pathological mechanism of IVDD. At the top, initiating factors like aging, trauma, genetic issues, obesity, infection and nutritional deficiencies disrupt ECM homeostasis. This leads to the upregulation of ECM-degrading enzymes and the loss of ECM components. In the middle are structural and cellular changes, including NP cell vacuolation, AF tears, NP extrusion, disc collapse and nerve growth with sensory sensitization. These changes ultimately result in discogenic LBP.⁴⁷ Copyright 2024 by the authors. Licensee MDPI, Basel, Switzerland.

An in-depth understanding of the pathological process behind disc herniation not only reveals the nature of the disease but also provides an important theoretical basis and design strategy for the application of polysaccharide-based hydrogels in disc repair. These strategies include: (a) repairing the AF; (b) restoring the function of NP; and (c) exerting anti-inflammatory and analgesic effects. Polysaccharide-based hydrogels directly address these unmet clinical needs through synergistic mechanisms: restoring disc hydration and biomechanics via biomimetic proteoglycan recruitment; preserving NP cell viability by delivering anti-apoptotic factors (e.g., TGF-β); breaking the inflammatory cascade by sequestering IL-1β/TNF-α; and providing structural reinforcement to mitigate spinal instability and nerve compression. This integrated approach establishes polysaccharide-based hydrogels as the next-generation paradigm for functional disc restoration.

3. Polysaccharide-based hydrogel for the treatment of IVDD

Polysaccharides are high-molecular-weight polymers composed of monosaccharides linked via O-glycosidic bonds and are widely distributed in nature. Their sources cover animals (such as chitosan and chondroitin sulfate), plants (e.g., cellulose), algae (e.g., alginate), and microbial metabolites (e.g., hyaluronic acid).⁴⁸ These materials feature core advantages such as biocompatibility, biodegradability, hydrophilicity and structural modifiability. Functional groups such as hydroxyl, amino, or sulfate on their molecular chain allow regulation of mechanical properties and degradation rates through chemical crosslinking or physical modification. In addition, polysaccharides closely resemble glycosaminoglycans (GAGs) present in the ECM of the intervertebral disc. This enables them to mediate cell adhesion and metabolic regulation through integrin receptors, so as to create a bionic microenvironment for tissue regeneration.⁴⁹ Different polysaccharides exhibit complementary properties and can act synergistically in IVDD treatment: (a) chitosan. It is derived from the deacetylation of chitin in crustaceans and contains positively charged amino groups that allow for pH-responsive sol–gel transformation. Therefore, it is suitable for the acidic microenvironment of degenerated intervertebral discs (pH 6.5–7.1). Its antibacterial and anti-inflammatory functions can inhibit postoperative infection and accelerate the repair of AF defects;^50,51 (b) as a natural component of GAGs, the sulfate group in chondroitin sulfate inhibits the activity of matrix metalloproteinases (MMP-3/13) through electrostatic interactions, thus preventing ECM degradation. Its high hydrophilicity simulates the hydration function of the NP and restores disc height and buffering capacity;⁵² (c) alginate: this forms shear-thinning hydrogels via calcium ion crosslinking, which offers both injectability and in situ gelation. It can conform to irregular intervertebral disc spaces under minimally invasive conditions. Its viscoelasticity matches native NP tissue and helps avoid stress-shielding effects;⁵³ and (d) hyaluronic acid (HA): With excellent water retention and lubricity, HA helps reverse dehydration and stiffening of degenerated NP tissue. Its CD44 receptor binding ability activates NP cells to synthesize type II collagen and aggrecan, promoting ECM regeneration.⁵⁴

In summary, polysaccharide-based materials provide an integrated treatment strategy for IVDD, addressing molecular repair and mechanical reconstruction. Based on their biomimetic physicochemical characteristics, capacity for biological function regulation, and improved clinical applicability, these materials demonstrate the potential as alternatives to traditional surgical interventions. In the following sections, we will discuss the specific applications of different types of polysaccharide-based hydrogels in the treatment of IVDD. By comparing their advantages, we aim to provide insights for future research and to further reveal hydrogel-based treatment for IVDD.

3.1. Hyaluronic acid-based hydrogel

HA is a natural polysaccharide and a widely used natural polymer in the biomedical field for its excellent biocompatibility, biodegradability, high hydrophilicity, moisture-retention capacity, and wound-healing properties. It is commonly employed as a base material for hydrogel dressings.^27,57 At the same time, its mechanical properties can be optimized by adjusting the degree of crosslinking and adding extra components to meet the mechanical needs of intervertebral disc tissues.⁵⁸

In substance delivery, HA serves as the core component. A self-healing injectable hydrogel is formed by crosslinking aldehyde-modified HA (HA-CHO) with poly(amidoamine) (PAMAM) through dynamic Schiff base bonds (Fig. 3A). This design overcomes limitations of traditional siRNA delivery systems, including low cellular uptake, short half-life and enzymatic degradation. The hydrogel's three-dimensional network provides physical confinement and a hydrophilic interface that protects the siRNA-PAMAM complex, which extends siRNA's half-life to more than three times that of traditional carriers. Moreover, the hydrogel realizes targeted slow release through the pH response characteristics of the inflammatory microenvironment.⁵⁵

Fig. 3 (A) An injectable, self-healing hydrogel enables sustained delivery of siRNA to silence the STING pathway, offering a gene-therapy strategy for IVDD⁵⁵ Copyright 2021 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd.; (B) The original, compressed, and recovered shapes of PBNPs@OBG hydrogel demonstrate its flexibility, as it withstands repeated stretching and compression without structural breaking⁴ Copyright 2022, The Author(s); (C) Schematic illustration of the synthesis of OHA-DA-PAM hydrogel from HA. Its three-dimensional network structure allows for injectability and self-healing, with potential for biomedical applications.⁵⁶ Copyright 2024 The Author(s). Published by Elsevier Ltd on behalf of Acta Materialia Inc.

Tang et al. developed a double-network composite hydrogel (GelMA/HA-His-Mg²⁺, GHHM) by integrating coordination crosslinking between histidine-functionalized hyaluronic acid (HA-His) with Mg²⁺ and a photo-crosslinking GelMA network. The dynamic coordination bonds in HA-HIS-MG not only offer the microspheres an excellent energy dissipation mechanism, but also create a “cell charging station” in the oxidative stress microenvironment of degenerated intervertebral discs through their ROS scavenging ability and sustained Mg²⁺ release. In vitro experiments showed that the dual crosslinked structure of GHHM significantly enhanced NP cell adhesion to 92% and maintained high cell viability.⁶¹ An injectable hydrogel named PBNPs@OBG (Prussian blue nanoparticles@oxidized hyaluronic acid/borax/gelatin) was constructed using a dual dynamic covalent crosslinking strategy (Fig. 3B). This hydrogel features rapid gelation, self-healing properties, and antioxidative capacity. The aldehyde groups of oxidized hyaluronic acid (OHA) form a dynamic Schiff base bond with amino groups in gelatin, while the cis-diol structure of OHA interacts with borax to form reversible borate bonds.⁴ This dual crosslinking strategy enables the hydrogel to recover its structure quickly after shear thinning and realizes accurate filling of irregularly shaped cavities in degenerated intervertebral discs.

A HA-based composite hydrogel (M2c-exos@HA hydrogel) loaded with M2c macrophage exosomes (M2c-exosomes) was constructed. The HA hydrogel formed a three-dimensional porous structure through hydrogen bonding and hydrophobic interaction, which realized prolonged exosome retention and release.⁶² Another injectable hydrogel, composed of HA and type II collagen (HA/COLII), was shown to relieve pain by suppressing aberrant sensory innervation, restoring disc hydration and extracellular matrix integrity, and allowing delivery via a single, minimally invasive procedure. As such, it offers a biocompatible and comprehensive therapeutic strategy for degenerative disc-related LBP.⁴⁷ Additionally, a blue-light-crosslinkable HA–collagen hydrogel loaded with FG4592 matches the mechanical properties of native NP and promotes the differentiation of BMSC into NP-like cells, offering an injectable platform for disc regeneration.⁶³ In another approach, a coiled HA–collagen I hydrogel microfiber that mirrors the micro-architecture of native AF, successfully guided BMSC differentiation toward an AF-like phenotype. This demonstrates the important role of matrix composition in cell fate determination and presents a scalable method for creating functional AF tissue constructs.⁶⁴ Furthermore, in a bovine disc organ culture model, a pilot study evaluated the use of an HA–platelet-rich plasma–batroxobin (HA/PRP/BTX) hydrogel as an injectable carrier for human mesenchymal stem cells (hMSCs). The hydrogel maintained hMSC viability, promoted differentiation toward the NP lineage, as evidenced by upregulated KRT19 expression, while preserving intrinsic disc metabolism.⁶⁵ These studies establish HA as a biological delivery carrier and a dual functional and structural regulator.

Stimuli-responsive hydrogels have great potential in the treatment of IVDD by facilitating localized and controlled drug delivery. A dual-stimulus-response (pH/ROS) hydrogel was constructed using a dynamic double-crosslinking strategy that involves oxidized OHA and phenylboronic acid-functionalized gelatin methacryloyl (GelMA-PBA). In this system, the aldehyde groups of OHA form dynamic Schiff base bonds with the amino groups of GelMA-PBA. The dynamic crosslinking conferred by HA gives the hydrogel three advantages: (a) enhanced tissue adhesion. The adhesion strength is 3 times higher than that of pure GelMA. This enables firm anchorage to the surface of the degenerated intervertebral disc through hydrogen bonds and covalent bonds; (b) controlled dual-stimuli-responsive drug release. There is a 50% increase in the loading capacity of diol-containing compounds and up to 85% release efficiency in an inflammatory microenvironment, supported by HA's natural free radical scavenging ability (ROS scavenging rate >90%); and (c) shear thinning-self-healing characteristics. Recovery rate of more than 95% ensures in situ gel formation after minimally invasive injection and compatibility with the biomechanical environment of the intervertebral disc.⁶⁶

NP-like differentiation remains a challenge in the application of stem cells for intervertebral disc repair. In this context, HA crosslinking plays a key role in the development of photo-crosslinked gelatin-hyaluronic acid methacrylate (GelHA) hydrogel, which has been shown to promote the differentiation of adipose stromal cells (ASCs) into NP-like cells. The crosslinked HA forms a stable, biocompatible three-dimensional network that supports cell adhesion and proliferation. In addition, crosslinking enhances the mechanical properties of the hydrogel and modulates the intracellular microenvironment through integrin αvβ6, thus promoting NP-like differentiation.⁶⁷ This strategy significantly improves the therapeutic efficacy of ASCs in disc repair by increasing NP matrix production and improving the disc height index. Overall, crosslinked HA hydrogels serve as a stable three-dimensional scaffold that enhances ASC survival, differentiation, and regenerative potential in the IVDD. With their excellent biocompatibility and mechanical stability, these hydrogels effectively support ASC proliferation and differentiation, thus enhancing their ability to repair degenerative intervertebral discs.⁶⁸

An injectable nanocomposite hydrogel was developed by crosslinking HA with aldehyde-modified HA (aldehyde-HA). This hydrogel modulates macrophage phenotypes, thus affecting the metabolic balance of the ECM. Specifically, the crosslinked HA not only provides a stable scaffold for hydroxyapatite nanorods, but also promotes the nucleation and osteogenic differentiation of mesenchymal stem cells, enhancing ECM synthesis. Additionally, it induces M2 macrophage polarization through epigallocatechin-3-gallate (EGCG), reducing ECM decomposition.⁶⁹ In another system, OHA was crosslinked with dopamine (DA) and polyacrylamide (PAM) to form a composite hydrogel with strong mechanical strength, bioadhesion, and self-healing ability. This crosslinked structure provides a stable scaffold for the modification of collagen mimetic peptide (CMP) and TGF-β1, while preserving the phenotype of AF cells by simulating ECM characteristics (Fig. 3C).⁵⁶ Furthermore, a vanillin-reinforced HA–collagen hydrogel (VCHA-NP) has been shown to effectively deliver IVDSCs, suppress inflammation, upregulate NP-specific markers, and restore disc height/biomechanics in 8 weeks, making it an injectable NP substitute.⁷⁰

Although HA-based composite hydrogels show multi-dimensional innovative applications in the treatment of IVDD, their excellent biocompatibility and suitability for drug delivery remain their prominent features. Therefore, in recent years, research on HA-based hydrogels has far outnumbered that on hydrogels derived from other polysaccharide materials. However, HA-based hydrogels are prone to degradation. To address this, dynamic crosslinking strategies, such as Schiff base bonding, borate ester formation, metal coordination, or enzymatic crosslinking, significantly prolong degradation times. Current studies have confirmed the potential of HA-based hydrogels to reverse disc degeneration through “mechanical-biological coupling” and “anti-inflammatory-regenerative synergy”. However, there are challenges for clinical transformation. Therefore, it is necessary to further explore intelligent crosslinking networks (such as optical/magnetic remote control), individualized manufacturing technologies, and long-term efficacy evaluation in large animal models. Furthermore, interdisciplinary integration, such as organ-like technology and bioelectronic monitoring, can promote HA hydrogel from “functional substitution” to “precise regeneration”, serving as a basis for a novel hydrogel-based regenerative strategy targeting intervertebral disc repair.

3.2. Chitosan-based hydrogels

Chitosan, derived from the partial deacetylation of chitin, exhibits excellent properties, strong adhesion, and favorable oxygen permeability. It is non-toxic and degradable, and shows great potential for applications in medical fields, such as medical antibacterial dressings.^51,73 Chitosan-based composite hydrogels have specific cationic characteristics that promote cell adhesion and growth. Their mechanical properties can be adjusted by changing the formulation ratio and crosslinking conditions. Additionally, these hydrogels offer good stability and processability.⁷⁴

In recent years, chitosan-based injectable hydrogels have attracted increasing attention for IVDD repair for their mechanical properties, which closely resemble those of the native NP, as well as their ability to support cell survival and proteoglycan synthesis. Recent studies show that the mechanical properties of chitosan hydrogel can be optimized through the incorporation of gelatin and Link N (LN, a naturally occurring peptide found in cartilage and the intervertebral disc extracellular matrix). These components synergistically enhance the hydrogel's bioactivity in the degenerative microenvironment. In particular, chitosan–gelatin composite hydrogels exhibit improved efficiency in incorporating LN and gelatin under degenerative conditions, significantly improving GAG formation.⁷⁶ On this basis, Huang et al. developed a double-crosslinked hydrogel (CSMA-PEGDA-L) by combining photo-crosslinked methacrylated chitosan (CSMA) with aldehyde-functionalized polyethylene glycol (PEGDA) through Schiff base reactions. This system enables rapid in situ molding by combining photocrosslinking with dynamic chemical bonds. The compressive strength of CSMA-PEGDA-L is significantly higher than that of hydrogels formed by either single photocrosslinking (CSMA-L) or single Schiff base crosslinking (CSMA-PEGDA) (Fig. 4A). The rapidly curing CSMA-PEGDA-L hydrogel seals IVDD defects with superior mechanical integrity, minimal cytotoxicity, and proven efficacy in slowing disc degeneration in rat tail models.⁵⁹ This study introduces an innovative double-crosslinking strategy to enhance mechanical adaptability, which provides a new approach for injectable hydrogel to immediately seal disc defects and block the vicious cycle of mechanical-biological degeneration.

Fig. 4 (A) A rapidly in situ forming injectable chitosan/PEG hydrogel designed for IVDD treament⁵⁹ Copyright 2023 The Authors. Published by Elsevier Ltd; (B) the QCS-OST/Exos hydrogel system that promotes intervertebral disc regeneration.⁶⁰ Copyright 2023 The Authors. Published by Elsevier B.V.

Previous studies have primarily been limited to small animal models and short-term observations that spanned only a few weeks. In contrast, this study systematically evaluates for the first time the long-term therapeutic efficacy of a chitosan carboxymethyl cellulose hydrogel loaded with autologous ASCs in a large animal (sheep) model. An intervertebral disc injury was surgically induced, and six weeks after injury, the ASCs-hydrogel composite was injected into the lesion site. The follow-up observation extended to 12 months. This study confirmed for the first time in a large animal model that ASC-loaded hydrogel can achieve long-term structural stability and suppress the degenerative process of intervertebral disc injury, offering key evidence for clinical transformation.⁷⁹ Based on the excellent biological characteristics of chitosan, this study also introduces an injectable self-repairing hydrogel (QCS-OST) composed of quaternized chitosan (QCS) and oxidized starch (OST). This is designed for the sustained delivery of Exos (Fig. 4B). The hydrogel exhibits an optimal porous architecture, excellent biocompatibility, and sustained-release behavior. Moreover, its dynamic chemical crosslinking network confers self-healing characteristics, facilitating adaptation to the dynamic mechanical environment of the intervertebral disc. In a rat model of IVDD, the QCS-OST/Exos hydrogel can reverse the senescence phenotype of NP cells and upregulate the synthesis of key ECM components to realize partial reconstruction of the degenerative disc. Improvements included increased water content in the NP and in the structural integrity of AF. This study combines exosome therapy with dynamically crosslinked hydrogel, presenting a new paradigm for targeted IVDD treatment by addressing its pathological mechanisms through the regulation of cellular senescence.⁶⁰

In summary, research on chitosan-based injectable hydrogels for IVDD treatment continues to advance, showing comprehensive innovations from material design to clinical transformation. Native chitosan is generally insoluble in water and organic solvents, but it requires chemical modification to enhance its solubility. However, the above studies have shown that chitosan can be modified through various approaches, and the resulting materials not only retain their inherent antibacterial properties but also exhibit improved physicochemical characteristics.

3.3. Sodium alginate-based hydrogels

Alginate is a biopolymer material obtained from brown algae in the ocean, widely used in the field of biomaterials for its excellent biocompatibility, non-toxicity, hydrophilicity, and hemostatic properties.⁴⁸ Its high solubility in aqueous solutions, rapid gelation, excellent plasticity, and compatibility with biological systems make it an ideal candidate for the preparation of injectable hydrogels.^48,80 It exhibits rapid gelation, promoting convenient in situ gel formation in the body.¹⁸ Its porous structure facilitates nutrient diffusion and cell migration, and the degradation rate of the hydrogel can be controlled by adjusting the cross-linking density.⁷¹

Traditional CaCl₂ cross-linked alginate gel faces limitations in clinical applications due to its uncontrollable gelation rate and insufficient mechanical stability. In response, this study introduced a CaCO₃/glucono-δ-lactone (GDL) slow-release cross-linking system to construct a new alginate-based system with adjustable gel dynamics. This represents the first application of GDL's slow-release cross-linking strategy in intervertebral disc regeneration.⁸⁰ The polysaccharide-based hydrogel (MB-ALG) shows a unique advantage in IVDD treatment. The hydrogel overcomes the limitations of traditional therapy through the synergistic effect of “physical capture-chemical remodeling-biological regulation” (Fig. 5A). Structurally, its coarse surface efficiently captures aging cells within the disc microenvironment. Chemically, OH⁻ produced by hydrolysis reshapes the acidic microenvironment (pH 6.2) into a mildly alkaline (pH 8.0), disrupting the acidic niche that supports cellular senescence. This process, along with the action of H⁺, mitigates oxidative stress by scavenging ROS. Biologically, the sustained release of Mg²⁺ ions inhibits Ca²⁺ influx and modulates the Sirt1-p53 signaling pathway, thus reversing the senescence phenotype. Meanwhile, the PI3K/Akt/mTOR pathway, activated by a weak alkaline microenvironment, can promote cell functional recovery.⁷¹

Fig. 5 (A) The MB-ALG hydrogel exerts multifaceted therapeutic effects on IVDD. It releases Mg²⁺ and generates OH⁻, which together enhance cell adhesion and improve the ECM microenvironment. By regulating intracellular pH, Ca²⁺ channels and the mTOR signaling pathway, the hydrogel reduces oxidative stress and inflammation while promoting cell proliferation⁷¹ Copyright 2024, American Chemical Society; (B) The bio-conjugation reaction of cysteine-terminated peptides to alginate occurs in two steps. First, maleimide groups are added to alginate under controlled conditions and then reacted with the AG73 peptide. Second, the resulting maleimide-AG73-alginate is mixed with BCN-Az-cRGD - alginate and crosslinked using calcium ions to form a (cRGD/AG73) alginate hydrogel.⁷² Copyright 2021 Elsevier Ltd. All rights reserved.

Alginate-based composite hydrogels, when integrated with functional peptides, show multi-dimensional synergistic regulation of cellular behavior. The surface-modified cRGD peptide targets integrin receptors, which enhances cell adhesion and mechanotransduction (Fig. 5B). In contrast, the AG73 peptide promotes ECM remodeling by binding to the syndecan receptor, which synergistically activates signaling pathways related to the rejuvenation of NP cells. This modification significantly improves the viability and biosynthetic activity of degenerated cells (Fig. 5B). Moreover, it induces the expression of rejuvenation markers such as N-Cadherin and reverses senescence-associated functional decline. Furthermore, it dynamically modulates cell behavior according to culture conditions - supporting cell spreading and adhesion formation in two-dimensional culture, while maintaining multicellular aggregate structure under three-dimensional encapsulation. As such, it simulates the natural NP microenvironment. In addition, the degradation characteristics of alginate match the release kinetics of the peptides, which provides sustainable microenvironment support for long-term intervertebral disc repair.⁷² Hydrophobic curcumin encapsulated by polylactic acid nanoparticles, combined with the natural biocompatibility of alginate/gelatin hydrogels, ensures sustained drug release while balancing mechanical properties and printability. The nanoparticles enhance curcumin's stability and cell uptake efficiency. At the same time, the calcium ion-crosslinked hydrogel network imparts shear-thinning characteristics suitable for 3D bioprinting, and significantly inhibits secretion of the inflammatory cytokine TNF-α in THP-1 cells, exhibiting low cytotoxicity. This design addresses the challenges of hydrophobic drug delivery and supports the fabrication of complex, customizable structures with anti-inflammatory functionality. This offers an intelligent platform for tissue repair in inflammatory microenvironments.⁸¹

A novel thermosensitive hydrogel based on poly(N-isopropylacrylamide-graft-chondroitin-sulfate) (PNIPAAM-g-CS) shows multiple advantages for IVDD treatment. By loading rehydrated alginate particles (diameter 20 ± 6 μm, concentration 50 mg mL⁻¹), the temperature-sensitive hydrogel accurately regulates its rheological properties and bioadhesive strength. It exhibits excellent injectability and in situ gelation, which meet the requirements for minimally invasive implantation. The hydrogel's compressive mechanical properties are significantly improved, which can restore the biomechanical stiffness of the degenerated intervertebral disc to near-normal levels and resist NP extrusion during lateral bending. Furthermore, the polysaccharide components, such as chondroitin sulfate and alginate, impart inherent biological activity, which supports the survival, proliferation, and differentiation of loaded ASCs into an NP-like phenotype, thus promoting ECM regeneration.¹⁸

Alginate-based injectable hydrogel shows multi-dimensional innovation potential in IVDD treatment. Their natural biocompatibility, rapid gelation, and adjustable mechanical properties constitute core advantages. When combined with functional modifications, such as targeted regulation of double peptide cRGD/AG73, anti-inflammatory delivery of curcumin nanoparticles, and a temperature-sensitive composite system, these hydrogels achieve synergistic optimization of mechanical adaptability and biological activity.

3.4. Chondroitin sulfate-based hydrogels

Chondroitin sulfate is a sulfated glycosaminoglycan composed of repeating disaccharide units of N-acetylgalactosamine and glucuronic acid. It has a molecular weight from 10 to 50 kDa, high water solubility and strong hydrophilicity.⁸² This compound is widely distributed across vertebrates, invertebrates, and bacteria.⁴⁸ Studies have shown its excellent anti-inflammatory properties.⁷⁵

The composite hydrogel of HA and chondroitin sulfate shows unique advantages in IVDD treatment through synergistic anti-inflammatory and antioxidant mechanisms. Constructed via dynamic borate bonding and Diels–Alder reactions, this double cross-linked network hydrogel features injectability, mechanical strength, and pH-responsive drug release (Fig. 6A). Among them, HA provides a biocompatible scaffold, while dopamine modification confers high-efficiency antioxidant capacity. Sustained release of chondroitin sulfate effectively inhibits inflammatory factor expression and restores the balance between synthesis/catabolism in degenerative NP. Animal experiments show that this hydrogel significantly alleviates disease progression and delays tissue degradation in rat models.⁷⁵ Its innovation lies in the precise functionalization of the polysaccharide matrix to achieve dual regulation of inflammation and oxidative stress. Chondroitin sulfate-based composite hydrogels play a key role in NP regeneration by providing a microenvironment conducive to tissue repair, simulating the components of natural ECM. As the core polysaccharide component of the NP, chondroitin sulfate, in combination with type II collagen, forms a biomimetic scaffold that significantly enhances the matrix synthesis capacity of nasal chondrocytes (NCs). The experiment shows that the increase in the proportion of chondroitin sulfate in the hydrogel directly promotes the secretion of sulfated glycosaminoglycan and drives the specific deposition of type II collagen. At the same time, it preserves the rounded three-dimensional morphology of NCs, thus activating their potential to synthesize NP-like matrix.⁸³ This discovery highlights the indispensable role of polysaccharide-based hydrogel in regulating cell behavior and reconstructing tissue-specific ECM.

Fig. 6 (A) The design and application of a double-crosslinked HA/CS hydrogel system for the treatment of IVDD⁷⁵ Copyright The Royal Society of Chemistry 2023; (B) A scientific diagram with a light blue background and a clear layout shows the therapeutic application of the SCPG hydrogel in treating IVDD. The diagram details the sequential process, including material preparation (SAMA and GM@P2), SCPG hydrogel formation and in vivo validation using a rat IVDD model.²⁶ Copyright 2024 Wiley-VCH GmbH.

Although temperature-sensitive triblock copolymer hydrogels are mainly made of synthetic materials, their design concepts are highly consistent with the biomimetic strategies of polysaccharide-based hydrogels. Specifically, they aim to simulate the native microenvironment of the NP through a macroporous structure that supports the uniform distribution and long-term viability of NP cells, selectively promotes the deposition of type II collagen and sulfated glycosaminoglycan, inhibits the generation of type I collagen, and precisely reconstructs NP-like matrix. The hydrogel's favorable mechanical properties and injectability provide the basis for minimally invasive repair, while the introduction of chondroitin sulfate further enhances cellular functionality through its bioactive polysaccharide signaling.⁸⁴ Meanwhile, the composite hydrogel system of sodium alginate and gelatin microgels plays a key role in IVDD treatment through a spatiotemporally controlled drug delivery system. The hydrogel enables the rapid release of chondroitin sulfate and the sustained release of parathyroid hormone-related peptide (P2), “waking up” the dormant NP stem cells (NPSCs). This significantly enhances their biological activity and promotes their differentiation into functional NP cells, while alleviating oxidative stress damage. The polysaccharide characteristics of sodium alginate and chondroitin sulfate confer excellent biocompatibility (Fig. 6B). At the same time, the hydrogel's dual physical–chemical cross-linked network improves its mechanical strength and viscoelasticity, facilitating its adaptation to the biomechanical environment of the degenerative intervertebral disc.²⁶

Methacrylate chondroitin sulfate hydrogel (MCS) plays an important role in the construction of a biomimetic NP microenvironment. As a three-dimensional culture platform, MCS hydrogel combined with decellularized nucleus pulposus (DNP) particles provides tissue-specific ECM signals and supports the high-activity survival of NP cells. While DNP particles alone are insufficient to fully preserve the cell phenotype, the polysaccharide characteristics of the MCS hydrogel lay a foundation for integrating additional endogenous microenvironment components. Its photocrosslinking network enables customization of mechanical properties and degradation kinetics to meet the specific demands of tissue regeneration. It is confirmed that polysaccharide-based hydrogel is not only an ideal carrier for ECM components, but also bioactive interfaces that modulate cell-matrix interaction. Therefore, they serve as a core framework for the development of future intervertebral disc regeneration strategies that integrate mechanical support and biological instruction.⁸⁵

Chondroitin sulfate, as a sulfated glycosaminoglycan composed of N-acetylgalactosamine and glucuronic acid, plays a key role in IVDD treatment and NP regeneration owing to its anti-inflammatory activity, hydrophilicity, and biocompatibility. It forms a double/multiple crosslinking system through dynamic borate bond, Diels–Alder reactions, or photo-crosslinked networks, to achieve synergistic anti-inflammatory and antioxidant effects, spatiotemporally controlled drug delivery, and the construction of biomimetic microenvironments. These composite systems exhibit injectability, mechanical adaptability, and pH-responsive drug release, while effectively regulating cellular behavior to reconstruct tissue-specific ECM and significantly delay the progression of IVDD. Future research may further integrate chondroitin sulfate with other endogenous bioactive molecules and dynamic mechanical stimulation, and optimize the degradability and cell-instructive capabilities of polysaccharide-based hydrogels through targeted chemical modification. These developments are expected to offer a new direction for personalized intervertebral disc repair strategies that combine mechanical support, minimally invasive implantation and biological activity.

3.5. Other types of polysaccharide hydrogels

In addition to common polysaccharide materials, including chitosan, HA, and sodium alginate, increasing attention has been directed toward cellulose and gellan gum in the field of IVDD. Cellulose, a linear polysaccharide composed of β-1,4 glycosidic units, has become a research hotspot in its nanoscale form due to its excellent mechanical properties and biocompatibility.^86,87

Cellulose-based polysaccharide hydrogels show significant advantages in IVDD treatment. Their excellent biocompatibility and injectability support minimally invasive surgical procedures, while their rapid crosslinking characteristics ensure intraoperative stability. These hydrogels also provide a supportive microenvironment for the long-term survival and functional maintenance of loaded ASCs (Fig. 7A). In a large animal model (sheep), implantation of the hydrogel for 12 months resulted in significant preservation of intervertebral disc height, mitigation of degenerative progression, and inhibition of tissue degeneration, primarily by enhancing ECM regeneration.⁷⁷

Fig. 7 (A) Carboxymethyl cellulose hydrogel loaded Mn bioactive glass NPs-nucleus pulposus derived mesenchymal stem cells in the experimental model process of intervertebral disc degeneration⁷⁷ Copyright 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies; (B) The pH-controlled reaction (pH 8.5) between glycidyl methacrylate (GMA) and low-acyl gellangum (GG).⁷⁸ Copyright 2010 John Wiley & Sons, Ltd.

Gellan gum is a natural polysaccharide produced by microbial fermentation, characterized by its high thermal resistance (120 °C), acid stability, thermal reversibility, low usage requirements, and excellent overall stability. Therefore, it is widely used in the food and pharmaceutical fields.⁸⁸ In the context of IVDD treatment, polysaccharide-based hydrogels, such as methacrylic gellan gum (GG-MA), are of great therapeutic value. GG-MA hydrogel, constructed by ion and photo-crosslinking technology, combines biodegradability with mechanical properties. Compared to native gellan gum, GG-MA exhibits significantly improved mechanical strength, lower water absorption and degradation rate, making it possible to effectively simulate the biomechanical environment of native NP tissue (Fig. 7B). Physical and chemical characterization confirms successful methacrylate modification, while dynamic compression testing shows its ability to support intervertebral disc loading.⁷⁸ Polysaccharide-based hydrogels, such as gellan gum/polyethylene glycol diacrylate double network hydrogel (GG/PEGDA), play a central role in intervertebral disc tissue engineering. Their biomimetic design and functional characteristics provide key support for disc regeneration. Specifically, these hydrogels replicate the structure of NP tissue and enable uniform distribution of BMSCs, thus sustaining high cell viability and ensuring cell-driven tissue regeneration. Moreover, their porosity and mechanical properties can be accurately adjusted through 3D modelling to meet the requirements of dynamic physiological loading conditions. In a composite scaffold constructed through the integration of 3D printing and electrospinning technologies, polysaccharide-based hydrogels not only synergize with fibrous bundle layers but also promote ECM regeneration through biocompatibility and a biomimetic microenvironment. Animal experiments show that such a scaffold effectively maintains intervertebral disc height and facilitates tissue repair, highlighting the irreplaceable role of polysaccharide-based hydrogel in mechanical adaptation, cell delivery, and regeneration microenvironment construction. These findings present innovative solutions for personalized disc repair.⁸⁹

Research on cellulose and gellan gum in IVDD treatment is still in its infancy. However, their unique performance and synergistic advantages provide potential for future research.

4. Conclusions

HA-based hydrogels achieve mechanical adaptation and responsiveness to the microenvironment through dynamic crosslinking strategies. Their high hydrophilicity and biological functions mediated by CD44 receptors render them “symptomatic”. Chitosan-based hydrogels, by contrast, adapt to the acidic microenvironment of degenerated intervertebral disc through pH-responsive sol–gel transformation. Their antibacterial and anti-inflammatory functions, alongside dual crosslinking strategies, significantly improve in-situ stability. Long-term reparative efficacy has been demonstrated in large animal models. Sodium alginate-based hydrogels maintain long-term mechanical stability through injectability and shear-thinning characteristics combined with CaCO₃/GDL slow-release crosslinking system, while peptide modifications enable targeted regulation of cell rejuvenation phenotypes. Chondroitin sulfate-based hydrogel exerts anti-inflammatory effects by inhibiting MMP-3/13 activity and contributes to ECM construction when combined with type II collagen. However, its single application depends on a composite system to improve the mechanical strength and functional synergy. Cellulose, gellan gum, and other emerging polysaccharides overcome the traditional mechanical bottleneck. Their self-assembly characteristics and compatibility with 3D printing technologies provide a new path for personalized intervertebral disc repair.

However, the current research has limitations: (a) material limitations: the mechanical strength, degradation controllability and biological activity of a single polysaccharide hydrogel cannot meet the demands of dynamic physiological loading; (b) bottlenecks in clinical transformation: most studies are limited to small animal models, with insufficient long-term efficacy data in large animals. In addition, aseptic implantation techniques and standardized evaluation systems remain to be further improved; and (c) complexity of mechanism: the molecular mechanism behind the interactions between polysaccharide and cells/tissues remains to be further analyzed, and there is still a gap between biomimetic design and dynamic adaptation required by the pathological microenvironment.

5. Future outlook

Future research should focus on the following directions: (a) although polysaccharide-based materials exhibit excellent biocompatibility, current experiments are still partially limited to small-animal models. Considerable efforts are needed to evaluate material safety, bridge the translational gap to clinical applications, and address the differences in anatomical structure, cellular composition, and regenerative capacity between animal models and the human intervertebral disc. It is crucial to translate success in animal experiments into clinical outcomes; (b) given the complexity of clinical applications, customizing stiffness and elasticity of hydrogels based on polysaccharide type and modification strategy is crucial. Advanced techniques such as 3D bioprinting can contribute to the fabrication of complex intervertebral disc structures. However, the corresponding medical costs may be prohibitive. In response, future research should strike a balance; (c) in previous studies, drug-loaded polysaccharide hydrogels, especially those based on hyaluronic acid, have always been a research hotspot. Research has primarily focused on how to combine a wider variety of bioactive substances, such as growth factors, small molecule inhibitors, miRNAs, etc., with hydrogels to achieve multi-targeted IVDD treatment. Additionally, a key area for future research involves the development of precisely controlled drug release mechanisms through the incorporation of physical stimuli, such as adjusting ultrasound intensity or using exercise-induced mechanical stimulation; and (d) future research should further elaborate on the specific mechanism behind the action of polysaccharide hydrogels. This will help guide the rational design and material optimization. For example, single-cell sequencing technologies can be used to examine fibrochondrocyte-like AF cells and NPSCs. In-depth studies of signaling pathways, including the TGF-β/SKI/FOXO3 axis, the PI3K/AKT/FOXO3 pathway, and other pathways, will help clarify the mechanism behind the action of polysaccharide hydrogels and inform future material design.

In summary, polysaccharide-based hydrogels are developing from “passive filling” to “active regeneration”, which provides a full-cycle solution from molecular repair to mechanical reconstruction for IVDD through bionic design, functional compounding, and technological innovation. The convergence of materials science and regenerative medicine is driving the development of next-generation intelligent polysaccharide hydrogels. With continued development, these platforms hold the potential to overcome barriers to clinical translation, potentially advancing IVDD treatment from symptomatic relief toward functional regeneration.

Conflicts of interest

There are no conflicts to declare.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

Acknowledgements

We thank Tongji University for providing a suitable literature-search platform. The authors acknowledge financial support from the Science and Technology Commission of Shanghai Municipality (23ZR1449000) and the Shanghai Tenth People's Hospital Cultivation Grant for Clinical and Basic Integration Research (SYYYRH2025047).

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Footnote

† Jun-kuan Shan, Jia-qi Fang and Shu-Hao Liu contributed equally to this manuscript.

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