Cartilage degradation is one of the most prominent pathological features of OA. This process is complex and involves abnormal changes in multiple cellular and molecular mechanisms, severely affecting joint function. Articular cartilage, a crucial component of the joint structure, is mainly composed of chondrocytes and the extracellular matrix (ECM) (Zheng et al., 2023; Zhu et al., 2023). The main components of the ECM include type II collagen, proteoglycans, and a small amount of non-collagenous proteins. Under normal physiological conditions, chondrocytes can maintain the dynamic balance between ECM synthesis and degradation, enabling normal joint movement and function. However, in the pathological process of OA, the homeostatic balance of cartilage is disrupted. The catabolic process is significantly enhanced, while the anabolic process gradually weakens (Zeng et al., 2022). The matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) families play key roles in cartilage degradation (Zhang et al., 2023). When the joint suffers mechanical damage, MMP-13 and ADAMTS-5 are highly expressed. MMP-13 can specifically recognize and cleave the helical structure of type II collagen, breaking it down into small-molecule fragments. This disrupts the fibrous network structure of cartilage, leading to a decline in its mechanical properties. ADAMTS-5 mainly acts on aggrecan in proteoglycans, causing a large amount of proteoglycans to be lost from the ECM (Stack and McCarthy, 2016). The reduction of proteoglycans decreases the hydrophilicity of cartilage, making it unable to store water effectively and weakening its compressive resistance. As cartilage degradation progresses, the cartilage surface gradually shows fibrosis and cracks, and eventually, the full-thickness cartilage is damaged, exposing the underlying subchondral bone, which seriously affects the normal function of the joint (Ouyang et al., 2023).

In addition to the effects of MMPs and the ADAMTS family, the abnormal behavior of chondrocytes in the pathological environment of OA also accelerates the process of cartilage degradation (Li et al., 2021). In the inflammatory microenvironment, the anabolic function of chondrocytes is inhibited. Their ability to synthesize ECM components such as type II collagen and proteoglycans is significantly reduced, and they cannot replenish the degraded matrix components in a timely manner. At the same time, chondrocytes in the OA state are more prone to senescence and apoptosis. Senescent chondrocytes secrete a series of senescence-associated secretory phenotype (SASP) factors, which include various pro-inflammatory factors and catabolic enzymes, further exacerbating the inflammatory response and cartilage degradation (Lafont et al., 2023). The apoptosis of chondrocytes directly reduces the number of cells that can maintain the structure and function of cartilage, greatly weakening the self-repair ability of cartilage (Ibáñez et al., 2022).

Furthermore, abnormal changes in subchondral bone are closely related to cartilage degradation. During the development of OA, subchondral bone shows abnormal bone remodeling, manifested as osteosclerosis and changes in trabecular bone structure (Fang et al., 2021). These changes in bone structure lead to alterations in the joint mechanical environment, causing uneven stress distribution on the cartilage and further aggravating cartilage damage and degradation. Meanwhile, cytokines and growth factors released from subchondral bone can diffuse into cartilage tissue, affecting the function and metabolism of chondrocytes and promoting the process of cartilage degradation (Cho et al., 2021; Duan et al., 2020).

The inflammatory response is another crucial factor in the pathological process of OA. Synovitis not only exacerbates the inflammatory environment within the joint but also promotes further damage to cartilage and bone tissues. Research shows that approximately 50%–80% of OA patients develop synovitis (Syed et al., 2024). The presence of synovitis significantly deteriorates the microenvironment within the joint, leading to a large accumulation of inflammatory factors and further aggravating the damage to cartilage and bone tissues, creating a vicious cycle (Sewell and and Östör, 2022). Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) are key pro-inflammatory cytokines in the OA inflammatory response (Roseti et al., 2019). In OA joints, multiple stimulatory factors can prompt synovial cells, macrophages, and chondrocytes to secrete IL-1β and TNF-α. IL-1β can upregulate the expression of various catabolic enzymes, such as matrix metalloproteinases (MMPs) and members of the a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family, by activating the nuclear factor-κB (NF-κB) signaling pathway, thus promoting the degradation of the cartilage matrix. Studies have shown that after IL-1β stimulates chondrocytes, the expression of MMP-13 and ADAMTS-5 increases significantly, accelerating cartilage destruction (Protano et al., 2023). At the same time, IL-1β can also inhibit the synthesis of type II collagen and proteoglycans by chondrocytes, further weakening the structure and function of cartilage. TNF-α also has a powerful pro-inflammatory effect. It can not only enhance the angiogenic activity of synovial cells, leading to synovial tissue hyperplasia and pannus formation, which in turn erodes cartilage and subchondral bone, but also synergize with IL-1β to amplify the inflammatory response and exacerbate joint damage (Nees et al., 2019).

In addition to IL-1β and TNF-α, other inflammatory mediators also play important roles in the inflammatory response of OA. Prostaglandin E2 (PGE2), an inflammatory mediator produced by the cyclooxygenase (COX) pathway, shows a significantly elevated level in OA joints (Liu et al., 2023). PGE2 inhibits the proliferation and differentiation of chondrocytes and promotes their apoptosis by activating the cyclic adenosine monophosphate (cAMP) signaling pathway. Meanwhile, PGE2 can increase vascular permeability and promote the infiltration of inflammatory cells, further aggravating joint inflammation. Moreover, PGE2 is closely related to pain generation as it can sensitize nociceptors, making patients experience more intense pain. Reactive oxygen species (ROS) also play a significant role in the OA inflammatory response. In OA joints, factors such as the activation of inflammatory cells, mitochondrial dysfunction, and metabolic abnormalities lead to an increase in ROS production (Knights et al., 2023). ROS are highly reactive and can oxidize intracellular biomacromolecules, such as lipids, proteins, and DNA, resulting in cell damage. At the same time, ROS can activate signaling pathways such as NF-κB, further promoting the expression and release of inflammatory factors and forming a vicious cycle. Studies have found that the level of ROS in the synovial fluid of OA patients is positively correlated with the severity of the disease, indicating that ROS play a key role in the inflammatory progression of OA (Di Francesco et al., 2022).

Furthermore, the inflammatory response can trigger the infiltration of immune cells and synovial hyperplasia within the joint. In the early stage of OA, the synovial tissue shows mild inflammation, manifested as the hyperplasia of synovial cells and the infiltration of inflammatory cells (Chow and Chin, 2020). As the disease progresses, the synovial inflammation gradually worsens, and the synovial tissue undergoes obvious hyperplasia and thickening, forming pannus. Pannus can invade cartilage and subchondral bone, releasing various proteases and inflammatory factors and directly destroying joint tissues. Meanwhile, the aggregation of immune cells in the joint leads to the abnormal activation of the immune response, further exacerbating the inflammatory response and forming a self-perpetuating inflammatory cycle.

Despite the growing understanding of the pathological mechanisms of OA, there remains a lack of effective clinical treatments capable of reversing the disease progression. Current treatment modalities mainly encompass non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoid injections, physical therapy, and lifestyle interventions (Chalidapong et al., 2024). These are designed to alleviate symptoms and enhance the quality of life of patients. However, most of these approaches can only provide temporary pain relief and fail to halt or reverse cartilage degradation and the inflammatory response. For patients with advanced OA, joint replacement surgery represents an effective treatment option. Nevertheless, its high cost and potential complications limit its widespread application. Moreover, long-term use of NSAIDs and glucocorticoids may lead to a series of side effects (Braaten et al., 2022). For instance, NSAIDs can cause gastrointestinal ulcers, and both NSAIDs and glucocorticoids are associated with an increased cardiovascular risk (Assi et al., 2023). Additionally, glucocorticoids may contribute to further cartilage degeneration. Consequently, there is an urgent need to develop novel treatment strategies, which can slow down the disease progression, reduce side effects, and ultimately improve the overall quality of life for patients suffering from OA.

Natural polymer-based hydrogels exhibit unique advantages in the treatment of OA due to their excellent biocompatibility, biodegradability, and similarity to the extracellular matrix. These hydrogels are mainly derived from natural biomaterials such as polysaccharides and proteins, which can provide a favorable microenvironment for cells and promote tissue repair and regeneration. HA is a crucial component of joint synovial fluid and the extracellular matrix of cartilage, plays a significant role in natural polymer-based hydrogels. Composed of D-glucuronic acid and N-acetylglucosamine linked by β-1,4 and β-1,3 glycosidic bonds, HA possesses good hydrophilicity and lubricity (Yi et al., 2022). In the treatment of OA, HA hydrogels can function in multiple ways. On one hand, they can mimic the function of joint synovial fluid, increasing joint lubrication, reducing friction, thereby alleviating joint pain and improving joint function (Zhou et al., 2024). On the other hand, HA hydrogels have certain anti-inflammatory properties, which can reduce the inflammatory response within the joint and create favorable conditions for the repair of damaged tissues.

Chitosan (CS) is another commonly used natural polymer with good biocompatibility, antibacterial properties, and low immunogenicity (Lin et al., 2024). CS can gelate under physiological conditions, and the resulting hydrogel has a certain pore structure, which is beneficial for nutrient exchange and cell adhesion and proliferation (Xuexuan et al., 2021). Pan et al. (2020) found that injectable CS thermosensitive hydrogels can provide good lubrication for the joint surface by reducing friction with surrounding tissues. At the same time, it can promote the growth and adhesion of mesenchymal stem cells (MSCs), thus protecting articular cartilage. This property makes CS hydrogels have great potential in the treatment of OA, especially in promoting cartilage repair. Alginate is a natural polysaccharide extracted from brown algae, has good biocompatibility, low toxicity, and high gelation ability (Zhao et al., 2023). Alginate hydrogels are usually prepared by ionic cross-linking and can be used as cell carriers for tissue engineering and drug delivery. In the treatment of OA, alginate hydrogels can load various bioactive substances, such as drugs and growth factors, to improve the microenvironment within the joint.

In addition to the above-mentioned common natural polymers, other natural polymers are also used to prepare hydrogels for the treatment of OA. For example, collagen, one of the main components of the extracellular matrix, has good biocompatibility and osteoinductivity. However, its weak mechanical strength often requires compounding with other polymers (Vinikoor et al., 2023). Gelatin, a hydrolysis product of collagen, has biodegradability and biocompatibility, but its mechanical properties and moisture-absorbing properties limit its single application (Li et al., 2023). Fibrinogen polymerizes to form fibrin clots during tissue injury. It can serve as a carrier for cells and drugs, promote cell adhesion and proliferation, and regulate drug release, which is helpful for improving the joint microenvironment and promoting tissue repair (Shen et al., 2025).

Poly(N-isopropylacrylamide) (PNIPAm) is a typical temperature-sensitive synthetic polymer. Its molecular structure contains both hydrophilic amide groups (-CONH₂) and hydrophobic isopropyl groups (-CH(CH₃)₂). This unique structure endows PNIPAm with distinct temperature-responsive properties in water. At room temperature, PNIPAm exists as a homogeneous solution, facilitating injection. When the temperature rises to near body temperature, the polymer solution undergoes a phase transition and forms a three-dimensional hydrogel (Chen T. et al., 2025). This property enables in situ gelation in vivo, making it an excellent carrier for drug delivery and tissue engineering. For instance, when PNIPAm is used to prepare drug-loaded gels, it can slowly release drugs at body temperature, enabling continuous treatment of osteoarthritis (Porcello et al., 2023). However, PNIPAm has some limitations, such as poor biodegradability, low mechanical strength, and difficulties in precisely controlling drug loading and release patterns. To overcome these drawbacks, researchers often improve its performance by adding other polymers to form an interpenetrating network (IPN) and adjust its drug-loading and release behavior (Lin et al., 2022).

Polyethylene glycol (PEG) is a widely used and non-toxic synthetic polymer. It can be copolymerized with biocompatible polyesters. By regulating the composition and length of the hydrophilic PEG segments and hydrophobic polyester segments, the thermosensitivity of the hydrogel can be precisely controlled (Yang et al., 2021). For example, the BAB triblock copolymer PLGA-PEG-PLGA is formed by the ring-opening polymerization of lactide and glycolide using PEG-diol as a macro-initiator. At low temperatures, the hydrophilic PEG and hydrophobic PLGA self-assemble to form micelles. When the environmental temperature increases, the PLGA shell dehydrates and the micelles aggregate, forming a scaffold with different drug-release rates (Ding et al., 2025). This temperature-responsive drug-release property allows PEG-based hydrogels to achieve precise drug release at the site of joint inflammation, enhancing the therapeutic effect while reducing side effects on normal tissues. Polyacrylamide hydrogels are highly cross-linked three-dimensional acrylamide networks with excellent biocompatibility and water-exchange capabilities (Bliddal et al., 2024). Research shows that injectable polyacrylamide hydrogels can protect the cartilage surface and promote high-quality fibrocartilage healing, effectively alleviating the symptoms of osteoarthritis (Vishwanath et al., 2023).

Poloxamers are a class of water-soluble non-ionic triblock copolymers composed of hydrophilic polyethylene oxide and hydrophobic polypropylene oxide blocks, belonging to intelligent polymers. They are sensitive to external stimuli such as temperature, pH, and salt concentration (Mammella et al., 2024). In an aqueous solution, poloxamers form micelles with an ordered structure at appropriate temperatures and concentrations. As the temperature rises, the structural order of the micelles increases, causing them to transform from a sol state to a gel state (Jose et al., 2024). This unique property allows poloxamer hydrogels to not only be directly used as drug carriers but also to immobilize other drug-delivery carriers at the injury site, enabling controlled release of the loaded drugs.

Wang et al. (2022) developed an injectable system using a triblock synthetic hydrogel (3B-PEG IH, specifically PLCL-PEG-PLCL) loaded with neural epithelial growth factor-like protein 1 (Nell-1), and evaluated its therapeutic efficacy in temporomandibular joint osteoarthritis (TMJOA). The PLCL-PEG-PLCL hydrogel, a synthetic triblock copolymer, was physically mixed with Nell-1 rather than integrating the protein into its network structure. In vitro studies showed that this system regulated the expression of chondrogenesis-related genes, while in vivo experiments using TMJOA rabbits demonstrated its ability to prevent subchondral trabecular bone destruction, repair the proliferative and fibrous layers of the joint surface, and reduce uneven hyperplasia of the fibrocartilage layer. Among different formulations, the 20 wt% PLCL-PEG-PLCL hydrogel was identified as optimal. This study suggests that the synthetic PLCL-PEG-PLCL hydrogel, when combined with Nell-1, may reverse TMJOA-induced osteochondral degeneration via the Nfatc1-Runx3 signaling pathway, offering a promising minimally invasive approach for clinical TMJOA treatment.

Composite hydrogels combine the biocompatibility of natural hydrogels with the excellent mechanical properties of synthetic hydrogels, presenting unique advantages in the treatment of osteoarthritis. By combining natural and synthetic polymers, these hydrogels can integrate the merits of both and compensate for the shortcomings of single hydrogels, offering more effective solutions for osteoarthritis treatment (Xu et al., 2025a). Li et al. (2024) constructed a composite hydrogel scaffold by combining sodium alginate (SA) and HA, and combined extracellular vesicles derived from mesenchymal stem cells (MSCs) with icariin to form a combined therapy. This composite hydrogel not only has good biocompatibility but also synergistically promotes the proliferation and migration of MSCs and chondrocytes, inhibits the inflammatory response, stimulates the synthesis of cartilage matrix components, activates the chondrogenic ability of chondrocytes, and simultaneously inhibits cartilage degradation, thus effectively promoting the repair of articular cartilage defects. In this composite system, sodium alginate provides good gelation ability and cell adhesion sites, while hyaluronic acid enhances the lubricity and bioactivity of the hydrogel. The combination of the two creates an ideal microenvironment for cell growth and tissue repair.

Long et al. (2025) developed an injectable nanocomposite hydrogel system for miRNA-based cartilage repair in knee osteoarthritis, addressing the limitations of free miR-455-3p (rapid degradation, poor targeting, and off-target effects). The system comprises a cartilage affinity nanocarrier (CANC) encapsulated in a PCL-b-PEG-b-PCL hydrogel: the CANC uses 50% PEGylated G5 PAMAM dendrimers to load miR-455-3p, with chondrocyte-affinity peptides (CAP) and minimal “self” peptides (MSP) modifying to enhance cartilage targeting and evade macrophage uptake. In vitro studies confirmed its excellent stability, low cytotoxicity, superior cartilage penetration, and chondrocyte targeting. In vivo experiments in miR-455-3p knockout mice and a destabilization of the medial meniscus (DMM)-induced KOA model demonstrated that sustained, targeted delivery of miR-455-3p effectively rescued cartilage degeneration and prevented KOA progression, with high biocompatibility and no observed cytotoxicity in major organs.

In addition, Rui et al. (2023) prepared an in situ photocrosslinked silk fibroin hydrogel encapsulating olfactory ectomesenchymal stem cell-derived exosomes (Exos@SFMA). This hydrogel has excellent biocompatibility and flexible mechanical properties, which can effectively protect the surface of joint tissues. In a collagen-induced arthritis (CIA) mouse model, implanting this hydrogel can significantly reduce the follicular helper cell response and further inhibit the differentiation of B cells into plasma cells, thus effectively alleviating synovitis and joint degeneration. This study demonstrates that this silk fibroin hydrogel combined with exosomes provides a powerful treatment option for the treatment of OA.

Injectable hydrogels’ therapeutic performance in OA is profoundly influenced by their structural characteristics, particularly internal pore size and network interconnectedness. Pore size determines the capacity for drug loading and cell infiltration: Hydrogels with micron-scale pores (10–100 μm) facilitate the encapsulation of large biomolecules (e.g., growth factors) and promote chondrocyte or stem cell adhesion, supporting cartilage regeneration (Lin et al., 2025). For example, alginate hydrogels with 50 μm pores show enhanced MSC infiltration and chondrogenic differentiation compared to smaller-pored counterparts (Macdougall and Anseth, 2020). In contrast, nanoporous structures (<10 μm) are optimal for small-molecule drug delivery, preventing premature leakage while enabling controlled diffusion. Network interconnectedness (the degree of cross-linking and pore connectivity) governs mechanical stability and mass transport: Highly interconnected networks ensure efficient nutrient/waste exchange, critical for maintaining cell viability in regenerative hydrogels (Majidi et al., 2018). A study on HA-based hydrogels found that increased network connectivity (via optimized cross-linking) improved both drug release uniformity and the ability to support chondrocyte metabolism (Wang S.-J. et al., 2024). Conversely, poorly interconnected networks may lead to uneven drug distribution and limited cell survival, compromising therapeutic outcomes. These structural features are tightly linked to hydrogel functionality: For instance, a composite hydrogel with tailored pore size (30–50 μm) and high interconnectivity showed enhanced encapsulation of exosomes, prolonged release, and superior cartilage repair in OA models (Xia et al., 2022). Thus, optimizing pore size and network structure is essential for maximizing the therapeutic potential of injectable hydrogels in OA.

Selecting an appropriate cross-linking strategy is crucial for optimizing the mechanical properties, biocompatibility, and therapeutic efficacy of injectable hydrogels for osteoarthritis treatment. Different strategies offer distinct advantages and limitations, impacting their suitability for various clinical applications (Zhang et al., 2023). Table 1 provides a detailed comparison of chemical, physical, and multiple cross-linking methods, highlighting their representative examples, benefits, drawbacks, and suitable applications.

The complex pathological microenvironment of OA, characterized by elevated temperature, acidic pH, and abnormal enzyme activity, necessitates the development of intelligent hydrogels capable of responding to multiple stimuli. Stimuli-responsive injectable hydrogels have emerged as a promising strategy, enabling precise drug delivery and localized therapy by adapting to OA-specific cues. These hydrogels can be designed to respond to thermal, pH, enzymatic, or combined stimuli, addressing key challenges such as uncontrolled drug release and poor specificity. Below is a summary of representative examples of stimuli-responsive hydrogels, highlighting their material composition, functional design, and therapeutic outcomes in preclinical OA models (Table 2).

Injectable hydrogels for OA treatment must meet specific mechanical and viscoelastic criteria to adapt to the dynamic joint environment. Load-bearing capacity is critical: hydrogels should mimic the compressive modulus of native articular cartilage (0.5–10 MPa) to withstand cyclic joint loading, preventing premature deformation or failure. For example, composite hydrogels reinforced with nanocellulose exhibit enhanced compressive strength, maintaining structural integrity under repetitive motion (Chen et al., 2022).

Self-healing ability enables hydrogels to repair microdamage caused by joint movement. This property, often mediated by dynamic bonds (e.g., metal coordination or hydrogen bonds), allows hydrogels to reassemble their network after shear or compressive stress—an essential feature for long-term efficacy (Goncu and Ay, 2023). A recent study showed that a chitosan-hyaluronic acid hydrogel with self-healing properties retained 80% of its mechanical strength after 1,000 cycles of compression, outperforming non-healing counterparts in OA models (Wu D. et al., 2024). Lubricating properties are equally vital, as reduced friction alleviates joint stiffness and pain. Hydrogels incorporating hyaluronic acid or phospholipids mimic the lubricity of synovial fluid (coefficient of friction <0.01), improving mobility by minimizing cartilage-on-cartilage wear (Guo et al., 2025). For instance, HA-based hydrogels with surface-grafted lubricin exhibit superior lubrication, reducing friction-induced cartilage damage in vitro (von Lospichl et al., 2017). These mechanical and viscoelastic attributes—load-bearing capacity, self-healing, and lubrication—are thus integral to the design of effective intra-articular hydrogels, ensuring they not only deliver therapeutics but also directly mitigate OA-related mechanical dysfunction.

A critical application of injectable hydrogels in OA treatment lies in their role as cell delivery platforms for regenerative therapies, supporting stem cell or chondrocyte transplantation to restore damaged cartilage (Lei and Fan, 2025). These hydrogels act as biomimetic scaffolds that mimic the native extracellular matrix (ECM), providing a favorable microenvironment for cell viability, proliferation, and chondrogenic differentiation.

Cell viability maintenance is foundational: hydrogels with optimal porosity and interconnected networks facilitate nutrient diffusion and waste removal, ensuring >80% cell survival over 4 weeks in vitro (Liu et al., 2021). For example, a hyaluronic acid-collagen hydrogel loaded with mesenchymal stem cells (MSCs) maintained 90% viability in a rabbit OA model, outperforming cell suspensions alone (Zhu J. et al., 2022). Chondrogenic differentiation is guided by hydrogel composition and bioactive cues. Incorporating chondrogenic growth factors (e.g., TGF-β3) or ECM-derived peptides (e.g., RGD) into hydrogels promotes MSC differentiation into chondrocytes, as evidenced by increased expression of type II collagen and aggrecan (Sang et al., 2022). A recent study showed that a silk fibroin hydrogel functionalized with kartogenin enhanced chondrogenesis, with differentiated cells exhibiting a phenotype similar to native chondrocytes (Wang P. et al., 2024). Integration with host tissue is key for long-term repair. Hydrogels modified with adhesion peptides (e.g., GFOGER) improve cell-matrix and matrix-tissue interactions, enabling seamless integration with surrounding cartilage. In a murine OA model, an injectable hydrogel delivering chondrocytes showed 30% higher integration efficiency compared to non-modified hydrogels, reducing the risk of graft detachment (Zhao et al., 2024).