Feng He
Hongwei Wu
Bin He
Zun Han1
Lei Huang- 1Department of Orthopedics, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, Zhejiang, China
- 2Department of Critical Care Medicine, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China
Articular cartilage has limited self-healing ability, resulting in injuries often evolving into osteoarthritis (OA), which poses a significant challenge in the medical field. Although some treatments exist to reduce pain and damage, there is a lack of effective means to promote cartilage regeneration. Reactive Oxygen Species (ROS) have been found to increase significantly in the OA micro-environment. They play a key role in biological systems by participating in cell signaling and maintaining cellular homeostasis. Abnormal ROS expression, caused by internal and external stimuli and tissue damage, leads to elevated levels of oxidative stress, inflammatory responses, cell damage, and impaired tissue repair. To prevent excessive ROS accumulation at injury sites, biological materials can be engineered to respond to the damaged microenvironment, release active components in an orderly manner, regulate ROS levels, reduce oxidative stress, and promote tissue regeneration. Hydrogels have garnered significant attention due to their excellent biocompatibility, tunable physicochemical properties, and drug delivery capabilities. Numerous antioxidant hydrogels have been developed and proven effective in alleviating oxidative stress. This paper discusses a comprehensive treatment strategy that combines antioxidant hydrogels with existing treatments for OA and explores the potential applications of antioxidant hydrogels in cartilage tissue engineering.
1 Introduction
Osteoarthritis (OA) is a prevalent, progressive, multifactorial joint disease characterized by chronic pain and dysfunction (James et al., 2018). It is commonly observed in individuals over the age of 65 and affects approximately 16% of the global population (Cui et al., 2020). OA primarily manifests as joint pain, dysfunction, and deformity, most often impacting load-bearing joints such as the knee and hip. It is one of the leading causes of lower limb disability in older adults (Hunter and Bierma-Zeinstra, 2019).
Research indicates that the main pathological features of OA are cartilage damage and the destruction of the extracellular matrix (ECM) (Kulkarni et al., 2021). Articular cartilage, a supportive connective tissue within the joint, is crucial for normal bone growth, structural support, resistance to deformation, and joint lubrication (Abramoff and Caldera, 2020). It is predominantly composed of slowly dividing chondrocytes, which constitute 5%–10% of the total cartilage mass. These chondrocytes maintain the ECM, a tough gel-like substance containing collagen, proteoglycans, and matrix proteins (Krishnan and Grodzinsky, 2018). Unlike most body tissues, cartilage is avascular, lacks nerve supply and has a weak regenerative capacity. Chondrocytes rely entirely on the diffusion capacity of the ECM for the necessary nutrients. This nutrient limitation implies that although cartilage can bear heavy loads throughout life, it has minimal capacity for recovery after injury or disease (Zhou et al., 2017; Liu et al., 2021a). Consequently, the repair and regeneration of cartilage defects remain significant clinical challenges. Additionally, Synovial tissue plays a critical role in the inflammatory mechanisms of OA. Inflammation within the synovium leads to the release of pro-inflammatory cytokines and degrading enzymes, which hasten cartilage breakdown (Sanchez-Lopez et al., 2022). This sets off a detrimental cycle involving synovitis, cartilage degeneration, and subchondral bone alterations, exacerbating joint damage and intensifying OA symptoms (Kurowska-Stolarska and Alivernini, 2022).
Strategies to treat OA include lifestyle modification, physical therapy, medication, and surgical intervention. Lifestyle adjustments and physical therapy aim to improve joint flexibility and reduce pain. Medication typically involves the use of NSAIDs, but long-term use may cause side effects (Varga et al., 2017). In advanced stages of the disease or when other treatments have failed, surgical intervention may be required (Hunziker et al., 2015). Despite the beneficial outcomes of these interventions, the tissue formed is often fibrocartilage rather than the original hyaline cartilage, and surgery can have secondary consequences. Platelet-rich plasma (PRP), which has a high concentration of platelets, is also injected into the joint to treat knee osteoarthritis. This treatment leverages the growth factors in the plasma to promote cartilage regeneration. However, the effects have been mixed, with most patients not seeing significant improvement. Joint replacement is still required in the late stages of the disease (Jones et al., 2019). Autologous chondrocytes and mesenchymal stem cells have been studied for cartilage regeneration, but for cell injection therapy, the main issue is the rapid clearance of transplanted cells due to lack of adhesion to cartilage defects (Huey et al., 2012; Vonk et al., 2018).
Recent studies have demonstrated that for larger cartilage defects, organoid or 3D-printed cartilage scaffold transplantation is a promising approach for cartilage repair (Yang et al., 2020; Liu et al., 2021b). Hydrogels are the most commonly used materials for 3D-printed scaffolds. They not only provide components that mimic the ECM of cartilage but also simulate the biomechanical properties and three-dimensional structure of cartilage, promoting cell adhesion, proliferation, and differentiation. Ideally, a hydrogel could not only relieve the symptoms of OA but also enhance the regeneration of the cartilage defect (Ding et al., 2022). However, varying degrees of inflammation are commonly present in the OA joint cavity. Reducing the level of inflammation in the joint cavity is crucial for improving the regenerative performance of biological scaffolds (Tamaddon et al., 2018).
In this review, we explore the mechanisms by which ROS contribute to the pathogenesis of OA and discuss recent advancements in the development of antioxidant hydrogels as a novel therapeutic approach. We highlight the potential of these hydrogels to protect chondrocytes, reduce inflammation, and enhance cartilage tissue regeneration, providing a promising alternative to traditional OA treatments.
2 The role of ROS in the pathogenesis of OA
ROS have been increasingly recognized as pivotal contributors to the pathogenesis of OA (Li et al., 2012). The accumulation of ROS in joint tissues can disrupt cellular homeostasis, leading to oxidative stress, inflammation, and cartilage degeneration. Understanding the mechanisms of ROS generation and their biological impact is crucial for developing targeted therapeutic strategies for OA.
2.1 Generation and sources of ROS
ROS primarily include superoxide anion (O2−), hydrogen peroxide (H2O2), and hydroxyl radical (·OH). These are natural by-products of normal oxygen metabolism and play critical roles in cell signaling and homeostasis. They are generated under both physiological and pathological conditions (Sies et al., 2022). The primary sources of ROS in biological systems include mitochondria, peroxisomes, and the endoplasmic reticulum.
Mitochondria is the primary source of ROS, particularly superoxide anions (O2−), which are produced during the normal operation of the electron transport chain. Complex I and Complex III of the mitochondrial respiratory chain are the major sites of superoxide production (Hayyan et al., 2016). Peroxisomes produce hydrogen peroxide (H2O2) as a by-product of fatty acid oxidation and other metabolic processes. Catalase, an enzyme within peroxisomes, converts H2O2 into water and oxygen, thereby mitigating its potential damage (Basri İla, 2022). The endoplasmic reticulum produces ROS during the protein folding process, with superoxide and hydrogen peroxide being generated as by-products during disulfide bond formation (Smirnova et al., 2018).
Additionally, NADPH oxidase produces superoxide anions in phagocytes during immune responses by catalyzing the reaction 2O2 + NADPH → 2O2− + NADP+ + H+. Upon activation, the cytosolic components translocate to the cell membrane to form the enzyme complex (Begum et al., 2022). Xanthine oxidase, a key enzyme in uric acid metabolism, catalyzes the conversion of xanthine to uric acid, concurrently producing H+ and H2O2, thereby increasing ROS levels in the body (Bortolotti et al., 2021). Understanding the generation and sources of ROS is crucial for developing targeted therapies to mitigate oxidative stress-related damage in diseases like OA.
Previous studies have shown that in most OA microenvironments, there are varying degrees of elevated ROS levels. High levels of ROS can damage chondrocytes, leading to dedifferentiation, senescence, and apoptosis (Zhao et al., 2020). ROS and/or reactive nitrogen species (RNS) play significant roles in many physiological, biological, and pathological processes (Sies et al., 2022). ROS is not only by-products of normal cell metabolism but also essential components of cell signaling (Schieber and Chandel, 2014; Azzi, 2022). In a healthy state, the generation and clearance of ROS are dynamically balanced to maintain cell function and tissue structure stability. However, in a diseased state, this balance is disrupted, leading to abnormally elevated ROS levels that trigger oxidative stress (Sies and Jones, 2020). ROS plays a key role in the pathogenesis of OA by influencing the aging and apoptosis of chondrocytes, destroying the ECM, regulating cell signal transduction, and promoting inflammatory responses (Henrotin et al., 2005; Rahmati et al., 2017; Blanco et al., 2018; Bolduc et al., 2019; Yao et al., 2019; Zhang et al., 2021). Therefore, controlling ROS levels and alleviating oxidative stress in the hydrogel materials is a critical strategy for treating OA.
Therapeutic strategies for ROS include the development of novel biomaterials and drugs, utilizing antioxidants or specific therapeutic compounds. Hydrogels are an ideal carrier material due to their excellent biocompatibility, adjustable physicochemical properties, and effective drug delivery capability (Parmar et al., 2015; Vega et al., 2017). Recent research has focused on the development of antioxidant hydrogels to combat ROS-induced damage in OA. These hydrogels aim to protect chondrocytes, reduce inflammation, and enhance cartilage tissue regeneration. By applying these innovative materials, ROS damage in OA can be directly targeted, offering patients more effective treatment options.
2.2 Mechanisms of ROS in the pathogenesis of OA
Previous studies have shown that the progression of OA is significantly associated with oxidative stress and ROS. Oxidative stress exacerbates cartilage damage and degradation by promoting chondrocyte apoptosis and inflammatory responses (Ahmad et al., 2020). In articular chondrocytes, ROS are typically produced at low levels, primarily generated by NADPH oxidase. These ROS are crucial components of intracellular signaling and are essential for maintaining cartilage homeostasis. They regulate various processes including chondrocyte apoptosis, gene expression, ECM synthesis and degradation, and cytokine production (Rahmati et al., 2017; Yamamoto et al., 2016; Sun et al., 2021). The role of ROS in chondrocyte damage and the progression of osteoarthritis is illustrated in Figure 1.
Figure 1. The role of ROS in chondrocyte damage and osteoarthritis progression.
2.2.1 Effects of ROS on chondrocyte senescence and apoptosis
Elevated levels of ROS cause oxidative stress, leading to damage in the DNA, proteins, and lipids of chondrocytes (Grishko et al., 2009; Loeser et al., 2016; McCulloch et al., 2017). This accumulated damage activates multiple cellular senescence pathways, such as Pathways such as ERK and p38 MAPK drive chondrocyte dedifferentiation and senescence, while pro-inflammatory signaling. Particularly via NF-κB, exacerbates the inflammatory response and accelerates cartilage degradation and the development of degenerative diseases like arthritis (Hossain et al., 2022; Lepetsos et al., 2019; Choi et al., 2019). The feedback loop between inflammation and oxidative stress accelerates cartilage degradation and chondrocyte senescence. ROS damage the mitochondria, leading to the loss of mitochondrial membrane potential and the release of cytochrome c, which activates caspase family proteins, ultimately resulting in apoptosis (Wang G. et al., 2021). Mitochondria are not only a primary source of ROS but also one of their main targets. Excessive ROS inhibit the mitochondrial respiratory chain, reducing ATP production and causing mitochondrial DNA mutations. This establishes a vicious cycle where mitochondrial dysfunction and ROS production exacerbate each other, leading to cell damage and death (Blanco et al., 2018; López-Armada et al., 2006; Kim et al., 2010). Excessive ROS also induce ER stress, activating the unfolded protein response (UPR), which in turn activates CHOP (a transcription factor associated with apoptosis), thereby inducing chondrocyte apoptosis (Lin et al., 2021).
Autophagy and Apoptosis Imbalance ROS inhibit autophagy, a cellular degradation mechanism that allows cells to repair themselves by degrading and recycling damaged organelles and proteins. Autophagy is regulated by pathways like mTOR, which is a major regulator of cell growth and metabolism and a negative regulator of autophagy. Suppression of mTOR can activate autophagy and delay aging (He et al., 2023). When autophagy is inhibited, the accumulation of damaged components exacerbates oxidative stress and cell damage. Imbalances between autophagy and apoptosis may be a key mechanism leading to chondrocyte death (Sun et al., 2021; Chen et al., 2016).
Ferroptosis is a form of programmed cell death characterized by iron-dependent lipid peroxidation, with ROS playing a central role in this process (Su et al., 2019). Excessive ROS promote the peroxidation of polyunsaturated fatty acids, leading to the accumulation of lipid peroxides, a hallmark of ferroptosis. Iron generates more ROS through the Fenton reaction, further accelerating lipid oxidation (Zhang X. et al., 2023). The depletion of glutathione (GSH) and the inactivation of GPX4 are also crucial in this process, leading to chondrocyte death (Ruan et al., 2024).
2.2.2 Destruction of the ECM in chondrocytes
In OA, the excessive production of ROS exerts a dual effect on the ECM, leading to its destruction and inhibiting its synthesis. ROS radicals, particularly hydroxyl radicals (OH·), directly attack proteoglycans and collagen molecules within the ECM. This not only prevents the formation of collagen fibrils but also degrades existing collagen and alters its amino acid composition (Bates et al., 1984). ROS further exacerbate ECM degradation by activating matrix metalloproteinases (MMPs). MMPs are a family of at least 28 zinc-dependent endopeptidases capable of degrading all ECM components, including collagens, non-collagenous proteins, and proteoglycans (Rose and Kooyman, 2016).
ROS also promote the expression of inflammatory cytokines such as IL-1β and TNF-α, which stimulate the overproduction of MMPs, a major cause of cartilage loss. Current research indicates that MMP-1 and MMP-13 are primary contributors to ECM degradation. MMP-1 is produced by the synovial lining, whereas MMP-13 is produced by chondrocytes. MMP-13 is involved in the degradation of type II collagen and proteoglycans, thereby playing a dual role in ECM destruction (Yamamoto et al., 2016; Ryu et al., 2011; Mehana et al., 2019; Hu and Ecker, 2021).
Inflammatory cytokines like IL-1β and TNF-α also induce the expression and increase the activity of a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4), leading to ECM degradation, particularly of proteoglycans (Xue et al., 2013). Moreover, the accumulation of ROS affects chondrocyte function, reducing their ability to synthesize ECM components. Previous studies have shown that nitric oxide (NO) mediates the inhibitory effect of IL-1β on proteoglycan synthesis (Cipolletta et al., 1998). By decreasing the production of critical ECM components, ROS not only accelerate the degradation of the existing ECM but also inhibit the synthesis of new ECM, further exacerbating cartilage degeneration (Zhang et al., 2020).
2.2.3 The effects of ROS on synovial cells
In OA, synovial cells play a critical role in both the production of ROS and the amplification of inflammatory responses (Mathiessen and Conaghan, 2017). Synovial inflammation drives increased ROS generation, which, in turn, activates key signaling pathways such as NF-κB, leading to the upregulation of pro-inflammatory cytokines like IL-1β and TNF-α (Sanchez-Lopez et al., 2022; Kurowska-Stolarska and Alivernini, 2022). This exacerbates the inflammatory environment and creates a vicious cycle where ROS and inflammation perpetuate each other, causing progressive tissue damage. Moreover, ROS stimulate the expression and activation of MMPs, particularly MMP-1 and MMP-13, in synovial cells (Kwapisz et al., 2023). These enzymes are directly involved in the degradation of ECM components, such as type II collagen and proteoglycans, further contributing to cartilage destruction and joint degradation in OA. Additionally, the release of chemokines like IL-8 and MCP-1 attracts immune cells to the inflamed site, intensifying the inflammatory response and ROS production (Russo et al., 2014; Miller et al., 2012). This cascade of events drives both inflammation and tissue degradation, perpetuating a cycle of joint destruction that worsens the progression of OA.
2.2.4 ROS and antioxidant defense mechanisms
In OA, patients, the levels of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) are significantly reduced (Koike et al., 2015; Ighodaro and Akinloye, 2018). The reduction of these antioxidant enzymes leads to excessive accumulation of ROS, resulting in cellular and tissue damage. To combat oxidative stress, organisms have developed a series of antioxidant mechanisms, including enzymatic antioxidants (such as SOD, CAT, and GPX) and non-enzymatic antioxidants (e.g., vitamin C and E). These antioxidants neutralize ROS, maintaining redox balance within cells and protecting them from damage (Ighodaro and Akinloye, 2018; Halliwell et al., 2005). In OA patients, increased ROS production and associated oxidative stress levels have been observed (Altay et al., 2015; Ertürk et al., 2017). Conversely, the levels of antioxidant enzymes like SOD, CAT, and GPX are reduced in OA patients, confirming the role of oxidative stress in the pathogenesis of OA (Ostalowska et al., 2006; Altindag et al., 2007; Scott et al., 2010). In OA, elevated ROS production and associated oxidative stress are well-documented, while reduced levels of antioxidant enzymes exacerbate this imbalance, contributing to the pathogenesis of the disease (Chen et al., 2020). Proteins like SIRT1, which regulate oxidative stress and inflammation, also play a protective role by maintaining cartilage homeostasis and promoting chondrocyte survival under oxidative conditions (Sun et al., 2021). Downregulation of SIRT1 in OA further impairs the cell’s ability to combat ROS.
Other key regulatory proteins involved in antioxidant defenses include Nrf2 (Khan et al., 2018), which governs the expression of enzymes like SOD and CAT, and FOXO transcription factors (e.g., FOXO1 and FOXO3), which help regulate cellular survival under stress (Shen et al., 2015). AMPK also contributes to oxidative balance by supporting mitochondrial health and reducing ROS accumulation, but its activity is diminished in OA (Chen et al., 2018).
Enhancing these antioxidant defense mechanisms, particularly through supplementation of exogenous antioxidants, offers a promising strategy to slow OA progression and protect chondrocytes from oxidative damage. Additionally, targeting regulatory pathways like SIRT1 and Nrf2 could provide novel therapeutic approaches for managing OA by mitigating ROS-induced damage and preserving joint health (see Figure 2).
Figure 2. Antioxidant defense mechanisms for osteoarthritis.
3 Applications of antioxidant hydrogels in the treatment of OA
Antioxidant hydrogels possess several advantageous properties, including biocompatibility, biodegradability and physical stability, making them ideal for therapeutic use in OA. These hydrogels are specifically designed to scavenge excess ROS in the body. They offer significant benefits in their physicochemical properties, as they are typically made from biocompatible polymers such as polyethylene glycol (PEG) (Bryant et al., 2004), hyaluronic acid (HA), and gelatin (Yang et al., 2024), ensuring they do not cause immune reactions or toxicity during application. Many of these materials use natural or synthetic degradable polymers, such as chitosan (Rajabi et al., 2021), polylactic acid (PLA), and polycaprolactone (PCL) (Li M. et al., 2023), which gradually degrade and are metabolized in the body, avoiding the need for secondary surgery. Hydrogels also maintain good mechanical strength and shape retention, ensuring that they hold their structure and function during joint movement (Yang et al., 2020).
The working mechanisms of antioxidant hydrogels involve several interconnected processes that manage oxidative stress while also protecting cells and promoting tissue repair. First, these hydrogels provide a controlled release of antioxidants, allowing gradual scavenging of excess reactive oxygen species (ROS) to maintain oxidative balance and reduce long-term tissue damage (Valentino et al., 2022). Many antioxidant hydrogels are ROS-responsive, meaning they can detect elevated ROS levels and automatically release antioxidants or therapeutic agents. This ensures timely and precise antioxidant protection when oxidative stress is high (Wu et al., 2022). Beyond managing oxidative stress, these hydrogels offer critical protection to cells by inhibiting ROS-induced apoptosis and tissue degradation. They achieve this by mitigating inflammatory responses, chelating metal ions that drive ROS production, and regulating cellular signaling pathways (Xu et al., 2022; Zhang C. et al., 2023). In particular, antioxidant hydrogels protect mitochondrial integrity, preventing oxidative damage to the cell’s energy center. Additionally, they support cartilage ECM repair by promoting chondrocyte function, reducing MMP activity, and preserving the structural components of the ECM (Jiang et al., 2023). The detailed mechanisms and potential applications of antioxidant hydrogels for osteoarthritis treatment are outlined in Table 1. Moreover, we have created a figure that summarizes the various mechanisms and therapeutic applications of different types of antioxidant hydrogels in the treatment of OA (see Figure 3).
Table 1. Mechanisms and applications of antioxidant hydrogels in osteoarthritis treatment.
Figure 3. Mechanisms and therapeutic applications of antioxidant hydrogels in osteoarthritis treatment.
3.1 Hydrogels for scavenging ROS
The direct scavenging of ROS by hydrogels involves incorporating antioxidants that neutralize ROS, mitigating cellular damage and inflammation associated with osteoarthritis (OA). Antioxidants such as vitamin C and glutathione are known to react directly with ROS, reducing oxidative stress. Vitamin C, for instance, neutralizes free radicals by donating electrons (Na et al., 2006; Chang et al., 2015), while glutathione acts as a reducing agent, playing a crucial role in cellular redox homeostasis (Cheng et al., 2017). Polyphenols, such as hydroxytyrosol (Valentino et al., 2022) and (−)-epigallocatechin-3-O-gallate (EGCG) (Li H. et al., 2023), exhibit significant antioxidant activity. Hydroxytyrosol is known for its ability to protect chondrocytes from oxidative damage, while EGCG, the main active component in green tea, is recognized for its potent antioxidant properties that contribute to the reduction of oxidative stress in cells. Some antioxidants enhance the body’s antioxidant activity indirectly by activating the antioxidant enzyme systems, such as superoxide dismutase SOD and CAT. Selenium is an essential component of glutathione peroxidase, while zinc acts as a cofactor for SOD, promoting the activity of these enzymes. For instance, Injectable hydrogels containing selenium nanoparticles can continuously activate glutathione peroxidase, enhancing OA treatment (Hu et al., 2023). Cerium oxide (CeO2) nanoparticles are another powerful ROS scavenger, with their unique ability to switch between Ce3+ and Ce4+ oxidation states, mimicking the action of SOD (Nelson et al., 2016). In vitro experiments have shown that CeO2 nanoparticles can prevent H2O2-induced chondrocyte damage and exhibit superoxide dismutase-mimetic activity (Lin et al., 2020).
3.2 Hydrogels for cell and mitochondria protection
In the context of OA, both apoptosis and autophagy imbalances play critical roles in disease progression (Su et al., 2019). Cell-protective hydrogels are designed to shield chondrocytes from ROS-induced damage, regulate autophagy, and support mitochondrial function. By maintaining intracellular ROS levels and enhancing the cellular antioxidant defense system, these hydrogels help reduce apoptosis and promote cell survival. For example, hydrogels developed by Hao et al. possess superior ROS scavenging capabilities, providing a protective environment that preserves cell integrity under oxidative stress (Hao et al., 2023). Additionally, chitosan microspheres and photocrosslinked GelMA hydrogels encapsulating sinomenium (SIN) have been shown to regulate autophagy and improve OA progression by targeting chondrocytes (Chen et al., 2016).
Mitochondria-regulating hydrogels extend the protective role by specifically targeting mitochondrial dysfunction, which is intricately linked to OA pathology (López De Figueroa et al., 2015). These hydrogels are designed to improve mitochondrial function, reduce ROS production, and enhance cellular resistance to oxidative stress. This not only protects chondrocytes but also promotes tissue repair and regeneration. Liu et al. developed a hydrogel formulation incorporating microcapsules that enhance mitochondrial activity, breaking the cycle of cellular senescence in OA by delivering therapeutic agents directly to the mitochondria (Liu et al., 2023). Similarly, Xiao et al. (2024) reprogrammed macrophages using hydrogel microspheres, impacting mitochondrial function to reduce inflammation and cartilage matrix degradation.
Moreover, advanced hydrogel systems such as those developed by Shi et al. combine cell and mitochondrial protection mechanisms (Shi et al., 2022). These hydrogels protect chondrocytes from ROS-induced gene expression changes, maintaining anabolic activities essential for cartilage repair while simultaneously preventing the upregulation of catabolic genes. By incorporating bioactive molecules that regulate mitochondrial dynamics, these hydrogels restore cellular energy balance, enhance chondrocyte viability, and reduce apoptotic signals. Future research will likely focus on optimizing these delivery systems and exploring combination therapies to further enhance clinical outcomes in OA treatment.
3.3 Hydrogels for promoting cartilage repair and regeneration
These hydrogels aim to provide a favorable environment for the repair and regeneration of damaged cartilage by reducing oxidative stress and inflammation. Many hydrogels incorporate bioactive molecules that promote cell proliferation and differentiation, such as growth factors (Jain et al., 2019), or provide physical support to facilitate new cartilage formation (Yang et al., 2023). For example, Cheng et al. (2023) developed a double-network hydrogel with antibacterial and anti-inflammatory properties, enhancing cartilage repair by incorporating allicin and decellularized cartilage powder. Similarly, Chen et al. (2024) designed a nano-composite hydrogel with poly (gallic acid)-manganese (PGA-Mn) nanoparticles, which strengthens the hydrogel while scavenging ROS, protecting chondrocytes from oxidative stress. In addition, hydrogels like the silk-based design by Zhang et al. (2022), infused with polyphenols, support cartilage regeneration by reducing oxidative stress and modulating inflammation. Other hydrogels, such as those carrying bone marrow mesenchymal stem cells (BMSCs), promote chondrogenic differentiation and tissue repair, offering regenerative potential for damaged cartilage (Wu et al., 2023). Temperature-sensitive hydrogels and those mimicking the ECM of cartilage, like those based on hyaluronic acid or chitosan, further enhance chondrocyte survival and function. Hydrogels with manganese nanoparticles and oxidized sodium alginate reduce MMP-13 expression and maintain collagen production, improving joint lubrication and antioxidation (Chen et al., 2024). By combining anti-inflammatory, antioxidant, and regenerative properties, these hydrogels offer a multifaceted approach to restoring cartilage integrity, making them a promising tool in osteoarthritis treatment.
3.4 Hydrogels for inhibiting inflammation
Anti-inflammatory hydrogels play a crucial role in alleviating the progression of OA by reducing inflammation through various mechanisms, thereby preventing further joint damage. These hydrogels can locally release anti-inflammatory drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) (Miao et al., 2024), corticosteroids (Wang Q-S. et al., 2021; Seo et al., 2022), or natural anti-inflammatory molecules, ensuring the drugs act directly at the site of inflammation to improve efficacy while minimizing systemic side effects. Moreover, many anti-inflammatory hydrogels can modulate inflammatory signaling pathways by scavenging ROS, thereby inhibiting the production of pro-inflammatory cytokines, effectively reducing inflammation and tissue damage (Koh et al., 2020). Studies show that LDH@TAGel hydrogel is an inflammation-responsive carrier that protects chondrocytes from oxidative stress and apoptosis by activating the Nrf2/Keap1 system and the Pi3k-Akt pathway (Liu et al., 2024). Additionally, the ChsMA+CLX@Lipo@GelMA hydrogel degrades in the OA microenvironment, inhibiting inflammatory factors while releasing chondroitin sulfate, which promotes chondrocyte proliferation and cartilage repair (Miao et al., 2024). Similarly, the novel hyaluronic acid granular hydrogel (n-HA) exhibits enhanced resistance to degradation and can be injected less frequently, while still providing anti-inflammatory effects (Zhang C. et al., 2023). By reducing chondrocyte senescence and blocking TLR-2 expression and NF-κB activation, n-HA effectively attenuates inflammation and protects joint tissues. These hydrogels share the common feature of responsive drug or factor release in inflamed environments, and by reducing inflammation and oxidative stress, they protect chondrocytes and promote tissue regeneration.
4 Advancements in antioxidant hydrogel technologies for OA treatment
The development of advanced antioxidant therapies targeting ROS mechanisms, such as gene therapy, nanotechnology, and novel drug delivery systems, holds tremendous potential for OA treatment. Given that ROS play essential roles in both physiological and pathological processes—acting as key mediators in inflammation and oxidative stress—targeting these pathways can significantly influence OA progression. Studies have shown that regulating the production and clearance of ROS can prevent cartilage degradation, providing an effective intervention for OA (Davalli et al., 2016). Combining antioxidant hydrogels with existing OA treatments such as physical therapy, pharmacotherapy, and surgery could provide a more comprehensive treatment approach. Hydrogels, as one of the most promising biomaterials in biomedical applications, have shown significant progress in cartilage tissue regeneration. Serving as biological scaffolds, drug carriers, and delivery vehicles for stem cells, hydrogels can also be combined with nanomaterials for targeted delivery. These innovative constructs hold promise for improving the repair and regeneration of damaged cartilage in OA (Xue et al., 2022).
5 Challenges and future directions for antioxidant hydrogel applications
Given the central role of ROS in cartilage damage, the application of antioxidant hydrogels in cartilage tissue engineering presents exciting new research opportunities. Studies indicate that these hydrogels could dramatically improve cartilage repair by reducing oxidative stress and preventing further degradation (Forrester et al., 2018). However, challenges remain regarding their clinical translation, including potential toxicity, achieving redox balance, and ensuring stability and biocompatibility. Moreover, manufacturing costs and the complexity of hydrogel-based treatments pose additional hurdles (Almawash et al., 2022).
Future research directions should focus on developing more precise hydrogel constructs, such as nanospheres or hybrid systems that better mimic human cartilage structure. These advanced hydrogels should aim to provide seamless integration with native tissues, thereby promoting efficient cartilage repair and regeneration (Eleftheriadou et al., 2020). Furthermore, combining basic research with clinical applications will be crucial to advancing the development of antioxidant hydrogels. Collaborative efforts across disciplines could lead to significant breakthroughs, helping shift the clinical paradigm from traditional OA treatments to innovative, biomaterial-based therapies (Xu et al., 2020).
Shifting clinical perspectives toward incorporating these advanced antioxidant hydrogels in OA management will be vital in optimizing treatment strategies. A focus on innovation in cartilage repair technologies may redefine the future landscape of OA treatment, providing new hope for patients suffering from this degenerative disease (Lin et al., 2022).
Author contributions
FH: Writing–review and editing, Writing–original draft. HW: Writing–review and editing. BH: Writing–review and editing. ZH: Visualization, Writing–review and editing. JC: Visualization, Writing–review and editing. LH: Writing–original draft.
Funding
The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Abbreviations
OA, Osteoarthritis; ROS, Reactive oxygen species; ECM, Extracellular matrix; PRP, Platelet-rich plasma; MMPs, Matrix metalloproteinases; ADAMTS4, a disintegrin and metalloproteinase with thrombospondin motifs 4; NO, Nitric oxide; SOD, Superoxide dismutase; CAT, Catalase; GPX, Glutathione peroxidase; PEG, Polyethylene glycol; HA, Hyaluronic acid; PLA, Polylactic acid; PCL, Polycaprolactone; EGCG, (−)-Epigallocatechin-3-O-gallate; CeO2, Cerium oxide; SIN, Sinomenium.
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Keywords: osteoarthritis, hydrogels, reactive oxygen species, antioxidant activity, review
Citation: He F, Wu H, He B, Han Z, Chen J and Huang L (2024) Antioxidant hydrogels for the treatment of osteoarthritis: mechanisms and recent advances. Front. Pharmacol. 15:1488036. doi: 10.3389/fphar.2024.1488036
Received: 29 August 2024; Accepted: 16 October 2024;
Published: 25 October 2024.
Edited by:
Pier Maria Fornasari, REGENHEALTHSOLUTIONS, ItalyReviewed by:
Xuchang Zhou, Beijing Sport University, ChinaMiguel Pereira-Silva, University of Coimbra, Portugal
Copyright © 2024 He, Wu, He, Han, Chen and Huang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Lei Huang, 8019062@zju.edu.cn