The meniscus (Figure 1) is one of the most important components of the human knee joint (Pasiński et al., 2023), playing a critical role in shock absorption, enhancing joint stability, lubricating joint surfaces, and optimizing force transmission (Mameri et al., 2022; Adams et al., 2021). Meniscus injury remains a pervasive and costly clinical challenge, burden increasingly amplified by aging global populations experiencing natural tissue degeneration and rising rates of sports participation and associated trauma, together driving significant and escalating demand for effective interventions (Adams et al., 2021). Currently, meniscus injury treatments primarily include conservative and surgical approaches (Giuffrida et al., 2020), against this backdrop, conventional treatments present persistent limitations that fail to adequately address the scope of the problem. Conservative approaches like physical therapy offer symptomatic relief but fundamentally cannot initiate biological repair of torn tissue (Sari and Kurniawati, 2022). Surgical options represent a historical compromise: partial meniscectomy removes damaged sections to alleviate pain (Wang H. et al., 2024a) but inevitably diminishes the meniscus’s vital biomechanical functions, inevitably accelerating joint degeneration and osteoarthritis risk (McDermott and Amis, 2006). While suturing aims for anatomical repair, its utility is severely constrained by factors like tear location (particularly in the poorly vascularized inner zones), chronicity, and patient age, leading to variable success rates, complex recovery periods, and procedural risks like infection and non-union (Popper et al., 2023); crucially, even successful repair often cannot fully restore the native tissue’s complex structure and function, representing a significant therapeutic gap. Motivated precisely by these long-standing inadequacies–the unmet need to achieve biological healing of tears (especially in challenging zones) and restore functional, protective meniscus tissue to halt the cascade towards osteoarthritis-research has increasingly focused on tissue engineering and regenerative medicine strategies (Bian et al., 2022; Lombardo et al., 2021). Stem cell therapy and novel biomaterials hold theoretical promise. However, practical translation faces formidable barriers, including identifying reliable cell sources, designing scaffolds that effectively mimic the anisotropic biomechanical properties of the native meniscus while supporting cellular integration and tissue formation, and ensuring long-term safety and efficacy (Li et al., 2023); It is within this specific context of unresolved needs and defined knowledge gaps that Hyaluronic Acid (HA) hydrogel has emerged as a compelling solution (Li et al., 2019). Its inherent high biocompatibility and biodegradability provide a foundation. Functionally, HA hydrogel offers potential as an injectable cell or bioactive factor carrier, fostering cell migration, proliferation, and differentiation directly at the injury site (Gupta et al., 2019; Teng et al., 2021). Critically, it represents a platform uniquely positioned to address the core limitations identified above: by potentially matching biomechanical cues, regulating the local inflammatory milieu, encouraging controlled vascular in-growth specifically where beneficial, and providing structural support, HA hydrogel aims to create the precisely tailored microenvironment necessary for functional meniscus regeneration (Li et al., 2024).

This review will summarize research advances in HA hydrogel for meniscus repair. By examining its mechanism of action, application value, and current research status, it aims to provide a new theoretical foundation and technical pathway for meniscus injury treatment. Moreover, it will guide clinical applications and future research, holding significant importance in advancing meniscus repair therapies.

HA (HA), as a naturally occurring polysaccharide, has garnered significant attention in the biomedical field due to its unique structure and diverse functions (Yasin et al., 2022). From its chemical structure and biocompatibility to its mechanical properties, the characteristics of HA endow it with great potential for applications in tissue engineering (Tsanaktsidou et al., 2022), drug delivery (Buckley et al., 2022), and joint lubrication (Su et al., 2023). The following sections provide a detailed overview of the structure and properties of HA from three perspectives: chemical structure, biocompatibility and biodegradability, as well as mechanical properties and viscoelasticity.

HA hydrogels demonstrate diverse application prospects in the field of meniscal injury repair. For instance, a decellularized extracellular matrix (dECM)-based hydrogel system incorporating methacrylated hyaluronic acid (meHA) (Figure 3) has been developed for the precision repair of meniscal injuries (Lee et al., 2025). In vivo tests confirmed the biocompatibility of hydrogels and their integration with native meniscus tissues. Furthermore, advanced 3D bioprinting techniques enabled the fabrication of hybrid hydrogels with biomaterial and mechanical gradients, effectively emulating the zonal properties of meniscus tissue and enhancing cell integration (Figure 4). This study represents a significant advance in meniscus tissue engineering, providing a promising platform for customized regenerative therapies across a range of heterogeneous fibrous connective tissues. This innovative system represents a significant advancement in meniscal repair, effectively addressing the challenges posed by heterogeneous meniscal injuries. The study points out that traditional repair strategies often fail to replicate the complex zonal characteristics of meniscal tissue, resulting in suboptimal healing outcomes. However, although this novel hydrogel system shows promise for precision repair, the research did not investigate the potential long-term effects or durability of engineered tissues in clinical applications, which may constrain the translational relevance of the findings.

In exploring microenvironmental regulation mechanisms, the pentenoic acid-functionalized hyaluronic acid (PHA) hydrogel system provides a platform for investigating mechanotransduction cues in meniscal fibrochondrocytes (MFCs) within the context of meniscal injury repair (Burkey et al., 2023). By modulating the degree of substitution (DoS) of reactive alkene groups, researchers achieved tunable crosslinking density and physical properties (including hydrogel crosslinking density, swelling ratio, and compressive modulus), which subsequently influenced MFC morphology and promoted regenerative phenotypes. This approach highlights the potential of PHA hydrogels for optimizing cellular microenvironments to enhance post-injury meniscal tissue regeneration. The study also indicates that while the developed HA hydrogel system possesses adjustable crosslinked network properties, its degradation rate is inversely correlated with DoS levels (lower DoS = faster degradation), which may compromise long-term structural integrity in physiological environments. Crucially, regulating the surface elastic modulus of these hydrogels was proven to modulate MFC morphology, suggesting that softer hydrogels preferentially induce an inner meniscus-like phenotype. However, the engineered mechanical properties may not fully recapitulate the complex biomechanical niche of the native meniscus, potentially limiting their efficacy in driving functional tissue regeneration.

Current evidence suggests that HA hydrogels hold therapeutic potential for diverse cartilage-related injuries, including meniscal pathologies, through enhanced tissue preservation and mitigation of inflammation-associated damage. However, traditional articular cartilage repair strategies primarily provide short-term symptomatic relief while failing to regenerate functional hyaline cartilage, leading to repaired tissues and adjacent healthy tissues being susceptible to progressive degeneration and mechanical wear over time (Kowalski et al., 2022). Although the developed HA hydrogel shows promise in restoring compromised cartilage biomechanics and suppressing chondrocyte catabolic activity, critical gaps remain in its clinical translation. Relevant studies lack longitudinal data on hydrogel efficacy under physiological loading environments and have not addressed potential limitations across varying injury severities (e.g., focal defects vs advanced degeneration). Furthermore, the interplay between hydrogel degradation kinetics and sustained biomechanical support in weight-bearing joints remains uncharacterized.

In animal model validation, the hyaluronic acid/hydroxypropyl chitin (HA/HPCH) thermosensitive hydrogel demonstrated superior efficacy in promoting the repair of full-thickness meniscal tears in a rabbit model (Wang et al., 2024b) compared to other treatment groups, exhibiting excellent temperature sensitivity, biocompatibility, and enhanced capacity to promote cellular proliferation and migration (Figure 5). The study found that the 2% HA-chitin hydrogel containing transforming growth factor β1 (TGF-β1) displayed the highest glycosaminoglycan (GAG) production, indicating its enhanced ability for matrix formation. After injecting this hydrogel into a rabbit model of full-thickness meniscal tears, at 12 weeks post-implantation, the TGF-β1 + HA/HPCH composite hydrogel showed significantly improved meniscal repair outcomes (Figure 6). The newly formed tissue closely resembled normal meniscal tissue in both structural and biochemical characteristics, outperforming other tested hydrogel formulations and control groups.

Another class of promising materials is the polyvinyl alcohol/tannic acid/gelatin/HA (PTGH) hydrogel, which demonstrates favorable mechanical properties and biocompatibility for cartilage tissue engineering applications (Xiang et al., 2023). Although the study primarily focused on articular cartilage repair, the incorporation of HA suggests potential applicability in meniscal injury repair. In vitro cell culture results indicated that PTGH hydrogels exert no negative impact on chondrocyte viability and proliferation, supporting their utility in tissue regeneration contexts, including meniscal injury. However, the biocompatibility of gelatin- and hyaluronic acid-based hydrogels is compromised by rapid degradation kinetics, which may diminish their effectiveness as tissue-engineered scaffolds for cartilage repair and regeneration. Additionally, traditional gelatin and HA hydrogels exhibit suboptimal mechanical properties, limiting their application in load-bearing tissues such as articular cartilage.

HA hydrogels themselves can serve as scaffolds for cell-based therapies to promote meniscal injury repair. These hydrogels support cell culture, improve the microenvironment of mesenchymal stem cells (MSCs), and facilitate effective tissue regeneration. Findings from preclinical studies suggest that combining hydrogels with cell-based treatments may improve the outcomes of meniscus repair strategies (Li et al., 2023). The review highlighted significant variability in cell doses used in clinical trials (ranging from 16 × 10⁶ to 150 × 10⁶ cells), which may affect the consistency and comparability of results across studies. The average dose was found to be 41.52 × 10⁶ cells, indicating a lack of standardized dosing protocols that could impact the efficacy of cell-based therapies for meniscus regeneration. The study notes that while various therapeutic strategies, including co-culture systems and composite materials, show promise for meniscus tissue regeneration, the selection of appropriate strategies must be tailored to the specific nature of the injury. This suggests that no universal approach exists, and the complexity of injury patterns may limit the generalizability of preclinical findings to clinical applications.

To further enhance cellular function, one study investigated the effects of meniscal fibrochondrocyte-derived conditioned medium (CM) and transforming growth factor-β3 (TGF-β3) on transduced mesenchymal stem cells (t-MSCs) (Koh et al., 2017), aiming to enhance their chondrogenic potential for effective meniscal tissue engineering. The methodology involved expanding t-MSCs in CM and encapsulating them within a riboflavin-induced photo-crosslinked collagen-hyaluronic acid (COL-RF-HA) hydrogel, which functions as a cell-supportive scaffold to facilitate tissue regeneration. In vitro results demonstrated that the combination of CM and TGF-β3 significantly upregulated fibrocartilage-associated gene expression (e.g., COL2, SOX9, ACAN, and COL1) and enhanced the production of extracellular matrix (ECM) components critical for tissue repair. In vivo evaluations further revealed that CM-expanded t-MSCs treated with TGF-β3 exhibited optimal performance in cell proliferation, glycosaminoglycan (GAG) accumulation, and collagen deposition, achieving complete regeneration in a meniscal defect model. The study concludes that integrating CM with innovative biomaterial design substantially enhances the chondrogenic differentiation capacity of t-MSCs, thereby promoting meniscal regeneration. This research provides a promising approach to improving meniscal repair strategies, with the potential to improve clinical outcomes for patients with meniscal injuries. However, it should be noted that although the study demonstrated the effects of conditioned medium (CM) and transforming growth factor-β3 (TGF-β3) on transduced mesenchymal stem cells (t-MSCs), it provided limited insights into the molecular-level interaction mechanisms of these factors. The long-term implications of this therapeutic approach, including the durability of regenerated tissue and potential late-onset complications, remain unassessed, constraining the understanding of the proposed method’s long-term efficacy and safety. Furthermore, no direct comparative analysis was conducted between the proposed strategy and established meniscus repair techniques, such as allografts or synthetic implants.

HA hydrogels, distinguished by their exceptional biocompatibility, tunable mechanical properties, and ability to promote tissue regeneration, have emerged as highly promising ideal materials for meniscus repair, with significant progress also achieved in related clinical applications. Taking Hymovis^® (manufactured by Fidia Farmaceutici SPA) as an example, it is a hexadecylamide derivative of hyaluronic acid, formulated as a sterile, pyrogen-free, viscoelastic hydrogel for intra-articular injection. It has been used for treating patients with symptomatic knee osteoarthritis (Pavelka et al., 2020), hip osteoarthritis (Migliore et al., 2020), and meniscal lesions (Zorzi et al., 2014). Clinical trials have substantiated the positive clinical efficacy of such viscosupplements in patients undergoing arthroscopic partial meniscectomy. Studies have demonstrated that intra-articular injection of Hymovis^® effectively alleviates patient pain, improves joint mobility, and reduces the use of non-steroidal anti-inflammatory drugs (NSAIDs). The specific advances of Hymovis^® in the clinical application of meniscus repair will be detailed in the following section.

Despite demonstrating significant potential in meniscal injury repair, current research on hyaluronan-based hydrogels faces limitations in three key aspects: material properties, clinical study design, and scope of application. Firstly, insufficient mechanical strength (as mentioned in section 2.2.2), uncontrolled degradation rates, and functional simplicity hinder their ability to meet the demands of complex injury repair. Secondly, clinical studies are commonly constrained by small sample sizes, short follow-up periods, and a lack of rigorous control groups, compromising the reliability and generalizability of findings. Finally, their applicability remains limited primarily to mild-to-moderate injuries, with further restrictions imposed by individual variability and high costs, presenting barriers to personalized treatment and widespread clinical adoption. Therefore, the development of personalised treatment and the clinical translation of HA hydrogels in this field still face two core obstacles. One of these challenges stems from the complex anatomical structure and dynamic biological environment of the meniscus. The precise dimensions, curvature, and mechanical gradients of the injured area must be customised using high-precision MRI data, but the degradation rate of the hydrogel is difficult to match the highly variable concentrations of synovial inflammatory factors in individual patients. Additionally, biofunctional customisation faces a dilemma: high cross-linking density can bear weight but inhibits cell migration, while low cross-linking promotes regeneration but may cause rapid collapse. The practical requirement for low viscosity during arthroscopic injection further complicates the balance of material properties. On the other hand, cost and manufacturing bottlenecks permeate the entire chain from R&D to payment. Personalised manufacturing relies on expensive raw materials and processes, with regulatory and clinical translation costs being particularly prominent. Long-term MRI follow-up and cold chain transportation continue to drive up expenses.

Future research should prioritize optimizing the mechanical properties, degradation kinetics, and functional diversity of hyaluronan hydrogels; conducting large-scale, multi-center randomized controlled trials (RCTs) with extended follow-up to comprehensively evaluate efficacy and safety; and exploring their potential for complex injuries while integrating complementary therapeutic approaches to enhance repair outcomes. Additionally, refining manufacturing processes to reduce costs is essential to facilitate broader clinical implementation, thereby enabling safe and effective treatment for more patients.

Looking further ahead, future development directions for hyaluronan hydrogels in meniscal repair encompass three domains: 1) Materials science innovation (developing smart hydrogels responsive to pH/temperature/enzymes, functionalizing with cell-adhesive peptides or growth factor binding sites, and creating composites with collagen/chitosan to enhance mechanical strength, bioactivity, and multifunctionality); 2) Personalized medicine strategies (designing precision treatment plans based on individual patient profiles, utilizing biomarkers to assess injury severity and repair progression, and developing tailored delivery systems); and 3) Novel technologies/methods (leveraging gene editing like CRISPR-Cas9 to modulate cellular regeneration, integrating mesenchymal stem cells (MSCs) into hydrogel composite systems, and employing advanced imaging such as MRI for real-time repair monitoring). These innovations will drive efficient and precise applications of hyaluronan hydrogels, offering safer and more personalized therapeutic solutions.

Hyaluronan-based hydrogels exhibit substantial promise for meniscal injury repair and cell culture applications. Their capacity to mimic the native ECM, support cellular growth and differentiation, and deliver therapeutic agents establishes them as invaluable tools in tissue engineering. Despite persistent challenges, ongoing research and advancements in hydrogel technology hold significant potential to overcome current limitations, paving the way for clinical translation and widespread adoption in meniscal repair.