Fabrication techniques of curcumin-enhanced hydrogels: Impact on immune response, and their role in inflammatory-related diseases

1. Introduction

Inflammation is a natural phenomenon that is part of the defense mechanism against infection, injuries, and external stimuli (Ferrero-Miliani et al., 2007, Michels da Silva et al., 2019). Depending on the trigger, it can be divided into acute and chronic inflammatory responses. Acute inflammation is triggered immediately when there is a stimulus, such as infection or tissue damage (Hannoodee S, 2024). The stimulus triggers the production of cytokines, chemokines, and acute-phase proteins, which are involved in attracting migrating macrophages and neutrophils to the inflammation sites, thereby triggering the innate immune response. Neutrophils participate in the destruction of antigens via phagocytosis, releasing reactive oxygen species and cytokines (Hannoodee S, 2024, Germolec et al., 2018). The inflammatory process is regulated, promoting tissue repair while pain is induced, typically lasting for a few days. However, if the inflammation does not resolve within a few days, it can progress into subacute inflammation lasting for 2 to 6 weeks, with decreased levels of inflammation but increased pain in damaged tissue. If the inflammation is still evident, it progresses from subacute to chronic inflammation that lasts for months or years (Pahwa R, 2024). The chronic inflammatory stage records an increased infiltration of macrophages, lymphocytes, and plasma cells that replace the neutrophils. Lymphocytes, involving T and B cells that are part of the adaptive immune system, become involved, producing antibodies, cytokines, and immune complexes (Milenkovic et al., 2019, Cutolo et al., 2019). These cells release cytokines, growth factors, and enzymes that are involved in tissue damage and repair processes (Pahwa R, 2024).

While inflammation is an important aspect of the body’s defense mechanism, chronic inflammation can lead to other adverse symptoms and complications, such as body pain, arthralgia, myalgia, fatigue, tissue scarring, impaired wound healing, organ dysfunction, and frequent infections (Pahwa R, 2024). Moreover, inflammation has been identified as a key mechanism of action in many diseases. Both acute and chronic inflammation of the tissue is linked to many diseases involving multiple organs such as the heart, pancreas, liver, kidney, lung, brain, and more. The management of inflammation is not just about suppression, but also about restoring balance, as over-suppression of inflammation can impair the healing necessary for tissue repair. Modulating, rather than inhibiting, ensures the inflammatory response is appropriate to the type of injury or the disease progression, avoiding excess damage and delay in healing. Targeting inflammatory pathways offers a potential approach to alleviate a wide range of diseases. Therefore, inflammation must be effectively managed to prevent long-term health consequences.

Inflammation is usually managed with conventional treatments such as non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and statins (Pahwa R, 2024). These drugs, although effective, can cause unintended adverse side effects such as gastrointestinal issues, drowsiness, skin reactions, and headaches (Vonkeman and van de Laar, 2010, Buchman, 2001). As a result, exploring alternative treatment options that are safer with reduced side effects is crucial.

One promising strategy is the use of curcumin-enhanced hydrogels. Curcumin is the primary bioactive compound found in turmeric, demonstrating strong anti-inflammatory properties, making it a valuable candidate for the management of inflammation (Aggarwal and Harikumar, 2009). Although the therapeutic effects of curcumin are promising, curcumin is highly insoluble in water, which decreases its bioavailability (Suresh and Nangia, 2018). Curcumin is a highly hydrophobic compound with a very low water solubility. Poor dissolution results in decreased absorption across biological membranes, affecting curcumin’s therapeutic potential (Górnicka et al., 2023). Moreover, curcumin, once absorbed, undergoes rapid first-pass metabolism and elimination in the liver and blood plasma, where it is quickly conjugated to glucuronide and eliminated from the body, thus reducing the concentration of active curcumin in the system (Karatayli et al., 2025). To overcome these pharmacokinetic limitations of curcumin, hydrogels can act as protective carriers to protect and stabilize curcumin from rapid metabolism and elimination (Ali Redha et al., 2024, Tabanelli et al., 2021). Moreover, hydrogels are hydrophilic three-dimensional networks that can absorb large amounts of water. The polymeric network also provides physical encapsulation of hydrophobic compounds such as curcumin (Stachowiak et al., 2024). Although biomaterials enhance the therapeutic effects of curcumin, significant problems remain in formulating a stable and effective delivery method. The use of nanoparticles and hydrogels improves curcumin’s solubility and stability, but these technologies increase the complexity of the delivery system, thereby increasing the cost of production. Additionally, it is a challenge to achieve a controlled, sustained release of curcumin in specific tissues, affecting its therapeutic efficacy (Hamilton and Gilbert, 2023). The interest in the potential of curcumin hydrogels in ameliorating inflammation-related diseases and injuries has led to this review. This review highlights the potential of curcumin-infused hydrogels in treating inflammation-related injuries and diseases, different fabrication methods of curcumin hydrogels, the effects of hydrogel’s mechanical and physiochemical properties on inflammation, and future improvements to enhance the therapeutic efficacy of curcumin hydrogels.

2. Inflammation as a Key Mechanism in Disease Pathogenesis

Inflammation begins when pattern recognition receptors (PRRs) detect stimuli or injuries, activating pathways that release inflammatory markers and increase inflammatory cell levels. Key triggers include pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) released by damaged or stressed cells. PRRs such as toll-like receptors (TLRs) and NOD-like receptors (NLRs) activate MyD88-dependent pathways leading to increased transcription factors like NF-kB that regulate pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β, as recorded in Table 1 (Akira et al., 2001). Activating inflammatory pathways is a key component of the pathogenesis of many chronic diseases involving a network of mediators, cytokines, and intracellular signalling mechanisms (Kaminska, 2005). The NF-kB pathway plays a key role in immune responses, cell survival, and apoptosis, promoting inflammation when activated (Lawrence, 2009, Hayden and Ghosh, 2012). Similarly, the MAPK pathway, which is involved in kinases like ERK, JNK, and p38, regulates cell functions and cytokine production in response to stress and cytokines (Kaminska, 2005). The JAK-STAT pathway also contributes to inflammation by regulating cytokine signaling, particularly IL-6, and influencing immune responses (O’Shea et al., 2015). These pathways, along with cytokines, coordinate the immune response to regulate inflammation, which can be polarized into pro-inflammatory or anti-inflammatory responses (Turner et al., 2014). The complete functions and receptors of pro-inflammatory and anti-inflammatory cytokines involved have been recorded in Table 1.

Inflammation is a critical mechanism implicated in the onset and progression of numerous diseases, ranging from cardiovascular and metabolic disorders to autoimmune and neurodegenerative conditions. Both acute and chronic inflammation are seen in various organs, including the heart, pancreas, liver, kidney, lungs, and brain, contributing to the complications and severity of disease (Chen et al., 2018). Common diseases/injuries involving inflammation as a key mechanism include chronic wounds, cardiovascular disorders, neuroinflammation, and pancreatitis.

The most common mechanism of inflammation is observed in skin-related injuries/diseases, as the skin, being the largest organ, houses an active immune system and serves as the body’s first line of defense (Trompette and Ubags, 2023). Common inflammatory skin diseases include psoriasis, eczema, seborrheic dermatitis, and hives. These diseases are caused by the overactivation of immune cells producing pro-inflammatory cytokines such as TNF-α, IL-4, and IL-17 that play a key role in driving inflammation and disrupting normal skin homeostasis (Cianciulli et al., 2024). Apart from diseases, inflammation is also an important mechanism in the wound-healing process (Guo and Dipietro, 2010). The inflammatory phase recruits immune cells to the site of the wound to clear damaged cells through phagocytosis, allowing tissue repair (Eming et al., 2007). Although inflammation is needed, other factors like diabetes, impaired debridement, obesity, and bacterial infections can lead to uncontrollable inflammation and the formation of chronic wounds. Chronic wounds occur when the healing process is prolonged due to the wound remaining in the inflammatory phase for an extended period, causing an imbalance in pro- and anti-inflammatory cytokines. This prolonged inflammation disrupts normal tissue repair, leading to delayed healing and potential complications (Schilrreff and Alexiev, 2022).

Apart from the skin, the common inflammatory condition involving the cardiovascular system is atherosclerosis, caused by the rupturing of atherosclerotic plaques that trigger inflammation and the infiltration of leukocytes (Libby et al., 2010). Inflammation also contributes to the formation of plaque and the increased risk of myocardial infarction (MI) and cardiac injury (Askevold et al., 2014). Following MI, the innate immune system response activates inflammatory pathways that help clear necrotic cells and debris (Opie et al., 2006, Pfeffer and Braunwald, 1990) through NF-kB signaling via TLRs. TLRs recruit leukocytes and cytokines such as TGF-β and IL-10 to the site of the infarction (Hall et al., 2006). These leukocytes and cytokines mediate repair processes by controlling inflammation, supporting myofibroblast activation, and promoting extracellular matrix (ECM) deposition (Frangogiannis, 2014, Kaur et al., 2009). Similarly, type 2 diabetes, a disease closely linked with inflammation, records that hyperglycemia and insulin resistance activate pro-inflammatory pathways including NF-kB, MAPK, and JAK-STAT and inflammatory cytokines such as CRP, IL-1β, and IL-6, which trigger cardiovascular complications such as heart failure and stroke (Dinarello et al., 2010, Turner et al., 2014).

In other organs, inflammatory pathways play pivotal roles. Chronic pancreatitis is often associated with pancreatic cancer, which involves activating inflammatory cells such as macrophages and neutrophils that secrete pro-inflammatory cytokines that activate pancreatic stellate cells. Pancreatitis triggers the activation of NF-kB, MAPK, and JAK-STAT pathways (Manohar et al., 2017, Zheng et al., 2013). Apart from the pancreas, liver diseases caused by infections like hepatitis B and C or non-infectious triggers such as alcohol exhibit inflammation mediated by PRRs, responding to DAMPs and PAMPs and other cytokines and chemokines produced by Kupffer cells (macrophages) (Szabo et al., 2007, Brenner et al., 2013). This activates the inflammasome, a cytosolic protein complex that triggers caspase-1 to activate IL-1β and other cytokines (Szabo et al., 2007). Similarly, chronic inflammation in the lungs, as observed in conditions like chronic obstructive pulmonary disease (COPD) and asthma, leads to structural and functional impairment of the respiratory system, with cytokines such as TNF-α, IL-6, and IL-8, which cause systemic and pulmonary inflammation (Kawayama et al., 2016). The inflammatory response triggers signal transducer and activator of transcription 6 (STAT6) while initiating the release of cytokines IL-4 and IL-13 and differentiation of Th2 helper T-cells. STAT6 also mediates the B cell isotype switching to IgE and the polarization of macrophages to the M2 phenotype (Walford and Doherty, 2013). In the kidney, glomerulonephritis or chronic kidney disease (CKD) is caused by chronic inflammation, triggered by infections, ischemia, or immune dysregulation (Ernandez and Mayadas, 2016). CKD impairs the function of dendritic cells, macrophages and phagocytic activity while increasing the infiltration of macrophages, exacerbating inflammation. These cytokines trigger key inflammatory pathways, such as NF-kB and MAPK, which are activated by cytokines such as IL-1β and IL-18, DAMPs, TLRs, and other immune mediators (Sanz et al., 2010, Kon et al., 2011). The brain is also susceptible to inflammation. Neuroinflammation, while serving as a defense mechanism, can cause neurodegenerative diseases like Alzheimer’s and Parkinson’s when uncontrolled, primarily due to the activation of the microglial cells and the release of inflammatory cytokines such as IL-1, IL-6, IL-1β and TNF-α. These cytokines enhance neuronal damage and blood-brain barrier permeability leading to tissue damage and cell injury (Ekdahl et al., 2003, Adamu et al., 2024). The inflammatory pathways involved in these diseases and injuries can be observed in Fig. 1.

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Fig. 1.

Inflammatory pathways in various diseases and injuries.

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Traditionally, chronic inflammation is usually treated with NSAIDs and corticosteroids. The goal of treating inflammation is managing inflammation instead of suppressing it. These medications are too strong, potentially leading to adverse side effects such as drug resistance and immunosuppression that can be detrimental to the body’s defense mechanism (Mustafa, 2023). Moreover, certain inflammatory conditions may affect multiple inflammatory pathways that require different types of medication to target these pathways leading to adverse side effects on the body (Chen et al., 2018). The limitations of these treatments have led to the discovery of safer alternatives with reduced side effects.

GM-CSF, granulocyte-macrophage colony-stimulating factor; MNPs, mononuclear phagocytes (MNPs); CCL, CC chemokine ligand.

The figure illustrates the different inflammation mechanisms involving T-cells, B-cells, macrophages, and monocytes and the signaling pathways in various diseases and organs such as skin wounds, cardiovascular disorders, pancreatitis, chronic liver disease, COPD, CKD, and neuroinflammation.

3. Revisiting Curcumin and its Timeless Therapeutic Potential

Given the centrality of inflammation in these diseases, safer and more effective anti-inflammatory treatments with fewer side effects must be studied. Curcumin, a natural compound found in turmeric, is known for its medicinal properties such as antioxidant, anti-inflammatory (Lestari and Indrayanto, 2014), antimutagenic, antimicrobial (Reddy et al., 2005, Mahady et al., 2002), and anticancer properties (Wright et al., 2013). The medicinal properties of curcumin have been well established and actively used in Ayurveda, Siddha medicine, and traditional Chinese medicine for centuries however, the exact mechanism of action and the primary bioactive compound of curcumin have only recently been explored (Khajehdehi, 2012, Hewlings and Kalman, 2017). Curcumin has the potential to target signalling molecules involved in inflammatory diseases, pain, metabolic syndrome, and pulmonary and cardiovascular diseases due to its strong anti-inflammatory and antioxidant effects (Aggarwal and Harikumar, 2009, Kuptniratsaikul et al., 2014, Trujillo et al., 2013). Curcumin shows great promise for therapeutic development, as it is classified as a Generally Recognized As Safe (GRAS) substance with a stable metabolism and low toxicity (Nelson et al., 2017).

Curcumin’s noteworthy properties have led to significant studies on curcumin and its effect on many inflammatory-related conditions/diseases. The use of curcumin in wound healing has been recorded in many studies, proving its therapeutic potential. Curcumin’s anti-inflammatory properties significantly reduce inflammation, allowing the remodeling and healing of the skin (Akbik et al., 2014). It reduces pro-inflammatory cytokines such as TNF-α and IL-1, inhibits NF-κB activation via pathways like AKT, PI3K, and IKK, and interacts with TLR4-MD2 co-receptors (Farhat et al., 2023, Kumari et al., 2022). The antioxidant properties of curcumin also reduce ROS activity, promoting a faster rate of wound healing (Sathyabhama et al., 2022). The use of curcumin is not limited to wound healing and injuries but has shown significant results in inflammatory-related diseases.

In cardiovascular disease, curcumin could inhibit TLR4 expression in atherosclerotic plaques, reduce tumor necrosis factor-alpha (TNF-α), inhibit NF-kB activation, reduce expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1) (Zhang et al., 2018). Curcumin also successfully regulated miR-599, myeloid differentiation factors (Chen et al., 2022a). Moreover, curcumin could activate the p38 MAPK/Nrf2 signalling pathway, inducing HO-1 expression that inhibits vascular endothelial inflammation (Xiao et al., 2018, Soares et al., 2004). Curcumin also recorded positive outcomes in hyperglycemia by reducing NADPH oxidase activity, reactive oxygen species (ROS) and ICAM-1 while inhibiting Akt/NF-kB and PI3K pathways and IL-8 expression, mitigating inflammation-related damage and improving diabetic vascular inflammation (Zhang and Li, 2018, Li et al., 2016).

Curcumin’s therapeutic potential extends to other organ systems as well. In the pancreas, curcumin suppresses pro-inflammatory cytokines such as TNF-α and CRP and inhibits the MAPK signalling pathway, NF-kB activation, and levels of IL-6, TNF-α, and iNOS, thereby alleviating inflammation in acute pancreatitis. Similarly, in the liver, curcumin inhibits the activation of hepatic stellate cells that are implicated in liver fibrosis while targeting PDGF-bR, MMPs, TGF-β, PPARγ, TLRs, and miRNAs and reducing the severity of inflammation (Jazayeri-Tehrani et al., 2019). In non-alcoholic fatty liver disease (NAFLD), curcumin significantly lowers levels of inflammatory markers TNF-α, CRP, and IL-6 while increasing adiponectin levels and reducing macrophage infiltration in adipose tissue, alleviating obesity-linked inflammation (Jazayeri-Tehrani et al., 2019). Additionally, curcumin downregulates pro-inflammatory cytokines and STAT3 while activating Nrf2, proving a strong antioxidant defense. In hepatitis C, curcumin could inhibit the replication and infiltration of the virus in target cells through the suppression of the HO-1 gene and the AKT-SREBP-1 pathway (Zhu et al., 2008; Kim et al., 2010). Apart from the liver, similar outcomes are recorded in CKD treated with curcumin. Curcumin significantly reduces inflammatory cytokines such as TNFα, IL-6, C-reactive protein, and IL-1β while ameliorating proteinuria and injury to the kidneys and restoring Nrf2 activity (Ghosh et al., 2009, Shing et al., 2011). Curcumin could also inhibit COX-2 expression while reducing the NADPH oxidase expression that mitigates ROS production and significantly reduces the oxidate stress on the kidneys. Moreover, curcumin could reduce the infiltration of macrophages and inflammatory eicosanoids while reducing complement activation (Kon et al., 2011). Similar outcomes of curcumin downregulating pro-inflammatory cytokines such as IL-6, IL-8, TNF-α, NF-κB, TGF-β, and COX-2 are recorded in COPD cases (Yuan et al., 2018). Curcumin could also inhibit alveolar epithelial thickening, proliferation and airway remodeling while reducing the CS-induced inflammatory cell infiltration and secretion of cytokines in the airway (Reis et al., 2021, Yuan et al., 2018, Zhang et al., 2016). Curcumin also reduces ROS production via Nrf2 signaling and HO-1. The PGC-1α/SIRT3 and CO/p38 MAPK pathways were activated when treated with curcumin, thus improving mitochondrial function and autophagy (Tang and Ling, 2019, Huang et al., 2019). Moreover, curcumin also modulated the PPARγ-NF-κB signalling via the inhibition of NF-kB, leading to a reduction of airway inflammation when treated with curcumin (Li et al., 2019). Curcumin has also been recorded to have therapeutic potential in neuroinflammatory disorders. Curcumin can cross the blood-brain barrier (BBB), which allows curcumin to directly reach the neuronal sites (Garodia et al., 2023). Curcumin also activates the Nrf2, which promotes antioxidant defense while inhibiting the NF-kB pathway, reducing the production of inflammatory cytokines. Moreover, curcumin scavenges ROS and free radicals, mitigating oxidative damage (Khayatan et al., 2022). In terms of neuroprotective effects, curcumin prevents neuronal apoptosis and neuroinflammation while restoring homeostasis in glial and neuronal cells. Both in vitro and in vivo studies demonstrate the ability of curcumin to reduce neuroinflammation, enhance mitochondrial function, and prevent neuronal degeneration (Garodia et al., 2023).

The anti-inflammatory mechanism of curcumin in regulating the immune system is similar in most diseases that involve the modulation of inflammatory cytokines, activation of the Nrf2 pathway, antioxidant activity involving ROS, suppression of signalling pathways, and the inhibition of transcription factors.

Although curcumin has remarkable therapeutic effects, one of the most significant issues is curcumin’s bioavailability when ingested (Anand et al., 2007). This is primarily caused by poor absorption, chemical stability, rapid metabolism, and elimination. Addressing curcumin’s bioavailability involves identifying strategies to block its rapid metabolism and improve absorption (Hewlings and Kalman, 2017). Research has recorded the use of piperine, the active compound in black pepper, which has been shown to enhance the bioavailability of curcumin by inhibiting metabolic breakdown (Han, 2011). Additionally, curcumin is highly insoluble in water, further complicating its use in clinical applications (Górnicka et al., 2023). Overcoming these limitations requires innovative delivery systems such as nanoparticles or encapsulation in hydrogels to enhance curcumin’s stability and bioavailability (Stachowiak et al., 2024).

4. Curcumin Hydrogels in Inflammatory-related Injuries and Diseases

Incorporating curcumin into hydrogels represents a promising therapeutic strategy to manage inflammation-related injuries and diseases due to their enhanced bioavailability, sustained release properties, and the ability to target key inflammatory pathways. Hydrogels are hydrophilic polymers rich in NH₂, COOH, OH, CONH₂, CONH, and SO₃H hydrophilic groups in a 3D network that absorbs a large amount of water and swells in water (Bashir et al., 2020). Hydrogels are cross-linked using a physical or chemical cross-linked polymer network and consist of a large quantity of water with a low elastic modulus (Norioka et al., 2021). Hydrogels can be fabricated from natural polymers or synthetic polymers. Hydrogels are highly water-based and provide sufficient moisture while having the ability to absorb water as well. This characteristic of hydrogel is highly favorable in wound healing (Firlar et al., 2022). Mechanically strong hydrogels involve the integration of synthetic and natural polymers. Synthetic polymers provide mechanical stability, while natural polymers help in cell adhesion, biocompatibility, and biodegradability (Leng et al., 2019). The characteristics of hydrogels make them an ideal biomaterial for the encapsulation of curcumin.

Several studies have recorded the potential of curcumin hydrogels in ameliorating these diseases, see Table 2. The most common research on curcumin hydrogels is recorded in wound healing mechanisms. A study on injectable curcumin-loaded PCL-b-PEG-b-PC and hyaluronic acid (HA) significantly reduced inflammation and resisted bacterial infection while promoting tissue vascularization and wound repair (Zhou et al., 2021). The study recorded a continuous reduction in inflammatory cell infiltration within the first week and achieved complete resolution by day 14. This effect is linked to sustained curcumin releases, which suppress NF-κB–driven cytokines such as TNF-α and IL-6, thereby accelerating the shift from inflammation to tissue regeneration (Zhou et al., 2021). Although the study recorded good outcomes, PCEC and HA are known for their anti-adhesion properties that affect the hydrogel to properly adhere to the site of the wound (Chen et al., 2022b). This could hinder the absorption of wound exudates, leading to delayed wound healing due to the accumulation of pro-inflammatory cytokines. This limitation might affect the wound-healing process when applied in clinical settings (Peng et al., 2022).

A similar study using alginate and curcumin hydrogels revealed the improved migration of fibroblasts at the site of the wound, indicating an increased rate of healing, a decrease in infection and inflammation, revascularization and regeneration of the wound. Curcumin-alginate hydrogels could reduce MMP9, promote VEGF to support angiogenesis, and increase TIMP1 to regulate remodeling and prevent excessive inflammation (Zamani et al., 2024, Johnson and Wilgus, 2014, Huang et al., 2024). The study also identified a limitation, showing a decrease in pore size when curcumin is added, which may affect the hydrogel to absorb exudate in the wound. Optimizing the dosage of curcumin and ensuring its solubility is crucial to ensure a minimal effect on pore sizes (Zamani et al., 2024, Pinthong et al., 2023). Furthermore, the use of curcumin-loaded modified quaternary animated chitosan hydrogels in wound healing studies recorded the ability of the hydrogel to inhibit the growth of E. coli and S. aureus and regulate inflammatory response by inducing the polarization of macrophages to M2 phenotype to release anti-inflammatory cytokines such as IL-10 and TGF-β to promote the repair and remodeling of the tissue (Bai et al., 2024a). The hydrogel ensures sustained release of curcumin to ensure the macrophages are continuously exposed to curcumin to provide an anti-inflammatory response (Bai et al., 2024a). Modifying chitosan has its advantages, but the modification may lead to greater cytotoxicity, which may induce unnecessary inflammation at the site of the wound (Fabiano et al., 2020). To enhance the efficacy of curcumin, a study recorded the use of silver nanoparticles in guar gum and curcumin hydrogels. The silver nanoparticles significantly improved the migration of fibroblasts, increased antibacterial properties, and decreased in expression of IL-6, a pro-inflammatory cytokine. The hydrogel stimulated the formation of collagen involved in tissue remodeling and wound healing (Bhubhanil et al., 2021). The use of silver nanoparticles (AgNPs) in hydrogel has recorded success in inhibiting the formation of bacteria, but this hydrogel must undergo human clinical trials, as AgNPs could cause cytotoxicity if it has prolonged contact, allowing the penetration of particles into the body (Li et al., 2024). A preclinical study recorded a hydrogel fabricated using hyaluronic acid/curcumin that was tested in a murine model. The study recorded a reduction in inflammation while promoting angiogenesis and supporting re-epithelialization at the site of the wound, resulting in accelerated wound closure with minimal scarring. Although effective in wound healing, it did not fully inhibit the growth of P. aeruginosa (Khaleghi et al., 2023). Similarly, another preclinical study fabricated a PBS-modified gelatin/oxidized hyaluronic acid/curcumin (GOHA-Cur) that was cross-linked using borate ester reaction and Schiff base reaction. The GOHA-Cur exhibited good antioxidant and immunomodulatory properties. GOHA-Cur could promote macrophage polarization towards the M2 phenotype, downregulate proinflammatory markers (IL-1β, iNOS), and upregulate anti-inflammatory markers (ARG1, IL-10). An in vivo study recorded that reduced ROS, increased collagen deposition, angiogenesis, and controlled release rate led to faster transition from the inflammation phase to the remodeling phase. Although effective, the hydrogel treatment group did not have a comparison with a positive control (standard dressing) (Zhao et al., 2023). Apart from that, a hydrogel fabricated using modified gelatin and curcumin-coated gelatin nanoparticles (GelMA/AHA-Gel@Cur) was tested in vivo against mice. The hydrogel accelerated the closure of the wound, reduced inflammation while promoting collagen deposition and tissue remodeling. There might be potential immunogenic or cytotoxic effects of unreacted aldehyde groups in the hydrogel that need further evaluation (Fu et al., 2024). These preclinical studies further validate the potential of curcumin hydrogel as a therapeutic in wound healing.

In cardiovascular-related diseases, curcumin-loaded PLGA nanoparticles incorporated with rhCOl III hydrogels significantly reduced the levels of TNF-α and IL-6 while inhibiting cell apoptosis. The hydrogel could also enhance cell proliferation, forming new blood vessels (Hu et al., 2022). Although recombinant human collagen has been recorded in many tissue engineering applications, it still poses significant challenges, such as possible immunogenicity and lower mechanical strength, which may worsen in cardiovascular applications (Cao et al., 2024). A similar study using Fe₃O₄ nano gels (MNPs) incorporated with curcumin in N-isopropyl acrylamide and MAA polymer recorded reduced expression of heart failure markers and oxidative stress markers when curcumin nanoparticles were increased (Namdari and Eatemadi, 2017). The study also found that the curcumin-loaded magnetic hydrogel nanocomposite outperformed free curcumin in reducing heart failure markers, such as ANP, BNP, and β-MHC, which are involved in controlling oxidative stress. The encapsulation of curcumin improved its stability, controlled release, and increased its bioavailability (Namdari and Eatemadi, 2017). However, Fe304 is known for its large surface area, which may cause serious agglomeration under magnetic influence that may affect the interaction between cells and tissues, leading to reduced release of curcumin. Moreover, metal ions are not biodegradable, leading to possible toxicity over prolonged use (Cai et al., 2020). Another study incorporated curcumin into a mixed-composition Cur-FFE-ss-ERGD/GSH hydrogel and reported a significant reduction in collagen deposition, which improved cardiac function while suppressing apoptosis, allowing for myocardial remodeling and healing. The hydrogel could significantly reduce the expression of MMPs and TGF-β1 compared to curcumin alone (Chen et al., 2017b). The disulfide bonds used in the hydrogel are sensitive to redox environments; if it is exposed to extracellular reducing agents such as cysteine, thiol-containing proteins, and oxidized glutathione (GSSG), it can break the disulfide bonds, leading to the early release of curcumin before penetration into the wound tissue (Liang and Fernández, 2009, Vašková et al., 2023). Another study using exosomes as carriers of curcumin encapsulated in decellularized extracellular matrix (dECM) hydrogel recorded comparatively better results compared to curcumin or exosomes alone. The hydrogel inhibited the formation of myofibroblasts, thus preventing the amelioration of fibrosis. Moreover, the hydrogel promoted angiogenesis by upregulating FGF2, IGF1, and VEGF while reducing infarct size, thus improving cardiac repair after myocardial infarction (Wang et al., 2023). Although exosomes are generally considered biocompatible, their immunogenicity depends on their source. Exosomes are highly heterogeneous and carry bioactive cargo such as DNA, RNA, and proteins that may provoke an immune response depending on their source, which may interfere with wound healing. Moreover, exosomes possess short half-lives due to phagocytosis by macrophages that may limit the ability to deliver curcumin, thus affecting its therapeutic potential (Koh et al., 2023).

Apart from cardiovascular, curcumin hydrogel has been recorded in studies involving the liver. A study on hepatocellular carcinoma recorded the positive effect of glycyrrhetinic acid (GA) and curcumin hydrogel in inhibiting HepG2 cells (liver tumor cells). This outcome proves the potential of curcumin hydrogel’s anti-cancer properties (Chen et al., 2017a). However, it has been noted that prolonged exposure to GA can cause pseudo-hyperaldosteronism characterized by hypertension, hypokalemia, and suppression of plasma renin and aldosterone levels (Speciale et al., 2022). A similar study on hepatocellular carcinoma developed a thermo-sensitive hydrogel using poloxamer, polyethyleneglycol (PEG), and curcumin and recorded the inhibition of HCA-F solid tumors in mice models (Gao et al., 2014). The hydrogel ensures sustained local delivery of curcumin to maintain longer exposure of anti-inflammatory and antioxidant actions to the tumor microenvironment (Gao et al., 2014). In the study, the pH of the hydrogel was set to 6.0 to accommodate the curcumin’s stability. However, a slightly acidic pH might not match the tumor microenvironment’s physiological pH of (6.5-7.2). Thus, it could lead to reduced therapeutic efficacy in clinical applications (Lu et al., 2024). A study by Ning et al. (2018) also recorded the anti-cancer potential of Thiolate chitosan-PEG-PEGDA-curcumin hydrogel in inhibiting the growth of HepG2 cells without causing adverse side effects. The hydrogel could release curcumin slowly and more locally, which reduces toxicity and prolongs its therapeutic effects compared to free curcumin. The modification of chitosan using thiolate should be carefully considered, as thiolate polymers may cause toxicity due to residual impurities (Puri et al., 2020).

Curcumin hydrogels were also recorded in studies of acute kidney injury and CKD, which has been represented in Fig. 2. A study on CKD incorporated curcumin in a double network hydrogel containing gelatine-curcumin-zinc with polydopamine (DOPA). The hydrogel successfully ameliorated renal fibrosis while ensuring the revascularization of neo-blood vessels and the formation of neonatal renal tubules in rat models, leading to a potentially successful renal regeneration (Zhang et al., 2022). Although effective, gelatine-based hydrogels are easily affected by pH and temperature. At extreme pH, hydrogels become softer, while a firm hydrogel is observed in the isoelectric pH of 5-10. This factor should be carefully considered, as CKD could cause metabolic acidosis, creating a more acidic pH that may affect gelatine-based hydrogels (Goudie et al., 2023, Kaimori et al., 2022). Furthermore, curcumin hydrogels were also studied in neuro-related injuries. A study by Sun et al. (2023) fabricated curcumin-loaded lysine/PEG/PEGDA hydrogels for the treatment of traumatic brain injury (TBI) in rat models. The hydrogel successfully improved the neurological functions while reducing the neurological impairments from TBI. The hydrogel also improved the inflammatory response by lowering the GFAP-positive astrocytes and IBA-1-positive microglia to allow nerve regeneration in the brain. However, the use of lysine in hydrogels should be carefully considered as high concentrations of free amine may induce cytotoxicity that may affect cell viability and function in the long run (Khunmanee et al., 2024, Wang et al., 2004). A similar study on chronic peripheral neuropathy recorded the integration of curcumin and Pluronic F127 to form a gel that can be encapsulated in a thiol-HA-BPA hydrogel. The hydrogel improved locomotor and muscular functionality by reducing the hyperalgesia in nerve injury. The hydrogel significantly reduced the levels of TNF-α and IL-6 while inhibiting the expression of TRPV1 and iNOS, indicating an anti-inflammatory response. IBA-1 positives involved in microglia activation were ameliorated, resulting in improved nerve regeneration (Kong et al., 2023a). Although the use of Pluronic F127 has recorded positive outcomes, it is important to consider that Pluronic F127 is thermo-sensitive and may cause easy degradation at physiological temperature, affecting the duration of drug delivery (Lupu et al., 2023). Curcumin hydrogels hold endless potential in ameliorating inflammation-related diseases and injuries. Table 2 summarizes preclinical and clinical studies of curcumin hydrogel, further supporting its potential in ameliorating various inflammation-related diseases.

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Fig. 2.

Effect of curcumin hydrogel in inflammation-related diseases and injuries.

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iNOS, Inducible nitric oxide synthase; GFAP, glial fibrillary acidic protein; PCEC, poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone); IBA-1, Ionized calcium-binding adaptor molecule 1; TRPV1; Transient receptor potential vanilloid 1; dECM, decellularized matrix; PEGDA, Polyethylene glycol diacrylate; TNF-α, tumor necrosis factor; GPX, Glutathione Peroxidase; SOD, superoxide dismutase.

The noteworthy evidence of curcumin hydrogels in ameliorating inflammatory-related diseases and injuries (see Fig. 2) has paved the way for more research in this field. The limitations of curcumin can be addressed via the encapsulation of hydrogels using different and specific fabrication techniques of hydrogels that can improve its therapeutic potential. It is important to ensure that the fabrication technique is carefully considered to ensure efficacy in treatment.

The figure illustrates the different effects of curcumin hydrogel in inflammatory-related diseases and injuries such as CKD, hepatocellular carcinoma, TBI, wound healing, and cardiovascular disorders. The positive effects of the curcumin hydrogel include the increase of anti-inflammatory cytokines and improved therapeutic effects.

5. Cross-linking of Curcumin Hydrogel and Its Effects on Immune Response

The emergence of curcumin hydrogel in biomedical research is very apparent due to curcumin’s therapeutic potential. Hydrogels are a successful carrier of curcumin that enhances its stability and bioavailability when used in therapeutics (Madamsetty et al., 2023). Curcumin is known for its insolubility in water due to its hydrophobic nature, but shows higher solubility in polar aprotic (acetone, DMSO) and protic (ethanol, methanol) solvents (Priyadarsini, 2014). Surfactants have also been used to increase the solubility of curcumin to form micelles or vesicles (Naksuriya et al., 2014). Still, these micelles are unstable and undergo drug loss during administration, leading to reduced efficacy and treatment failure (Kamaly et al., 2016). Thus, a more stable formulation is the encapsulation of curcumin into water-soluble polymers such as hydrogel, which improves water solubility and drug retention while enhancing the stability of curcumin (Hawes et al., 2017). Several methods are used to encapsulate curcumin in the hydrogel, including covalent interaction, physical cross-linking, and simple diffusion/partitioning, see Fig. 3.

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Fig. 3.

Cross-linking methods of curcumin hydrogel and its effect on immune response.

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Covalent interactions involve a polymer, gel initiator, cross-linker, and the drug that is polymerized to form a stable matrix. This method involves strong covalent bonds to ensure higher drug encapsulation efficiency and stability by limiting the loss of curcumin through diffusion. A study on curcumin-phenyboronic acid (PBA) hydrogel was fabricated using the Hantzsch reaction via dynamic boronic ester linkages between curcumin and the polymer. A controlled release rate of curcumin can be achieved by modulating the borate-boronic acid equilibrium (Pan et al., 2021). A similar study fabricated the curcumin-PEG-DTE hydrogel using condensation polymerization using triphosgene and pyridine as catalysts. This method used a biodegradable carbonate linkage for the cross-linking of the hydrogel. This method significantly protects the curcumin from oxidation and degradation (Shpaisman et al., 2012). A study involving the fabrication of supramolecular hydrogels, which are GA-Cur and naphthyl acetic acid (Nap-Cur) modified curcumin pro-gelators that are formed through glutathione-triggered disulfide bond reduction. This method increases the solubility of curcumin and creates a sustained release of curcumin (Chen et al., 2017a). Covalent interactions also include chemical cross-linking of the hydrogel. A study recorded the fabrication of silk-curcumin hydrogel that was cross-linked using HRP/H₂O₂ mediated dityrosine bonding in silk fibroin (Sundarakrishnan, 2025). Other common chemical cross-linker used in the fabrication of curcumin hydrogel includes carboxymethyl chitosan and genipin (Ling et al., 2025). Chemical cross-linking provides a strong and stable hydrogel with good mechanical properties. Moreover, the gelation time of the hydrogel can be controlled based on the concentration of the enzyme and chemical cross-linker used (Sundarakrishnan, 2025). Covalent cross-linking produces hydrogels with greater mechanical strength and stability, resulting in a slow degradation rate (Priya et al., 2024). This slow degradation rate supports a longer-lasting release of curcumin, which provides prolonged anti-inflammatory effects, without sudden immune activation. Although it improves mechanical properties, these chemicals and enzymes may introduce toxicity concerns when used at high concentrations, which may affect their biocompatibility (Kong et al., 2023b).

Apart from covalent interactions, physical cross-linking is another method for encapsulating curcumin. Physical cross-linking includes ionic cross-linking, hydrogen bonding, freeze-thaw, and host-guest noncovalent interactions. Ionic cross-linking allows curcumin to interact with ionic polymers, such as alginate, when cross-linked using divalent ions like calcium (Ca²⁺). A study on the encapsulation of curcumin in alginate as a potential therapeutic for wound healing used calcium chloride as the ionic cross-linker to form the hydrogel (Zamani et al., 2024). Hydrogen bonding is another method where hydrogen bonds are formed when curcumin is integrated into the polymer. The phenolic and β-diketone groups of curcumin form hydrogen bonds with functional groups in polymers such as (-OH, -COOH, -NH₂). This bond creates a hydrogel that has strong mechanical properties and moisture-resistant properties (Lan et al., 2024). Ionic interactions enable more flexible release of curcumin because ionic bonds can be disrupted by changes in environmental conditions, such as pH or ionic strength (Shewan and Stokes, 2013). This allows for the fabrication of responsive hydrogels that release curcumin in response to local inflammatory conditions, such as an acidic pH at the site of the wound (Zhang et al., 2023). Moreover, curcumin hydrogels are also fabricated using the freeze-thaw method. Water crystallizes during freezing and forces polymers into a concentrated region. The crystals melt during thawing, but the polymer chains remain intact through the formation of crystallites and hydrogen bonding. The repeated cycles of freeze-thaw enhance its stability and mechanical strength (Pornpitchanarong et al., 2024). Freeze-thaw is a technique that is simple and cost-effective without the use of any toxic cross-linkers, minimizing the risk of curcumin degradation (Bernal-Chávez et al., 2023). Moreover, freeze-thaw increases the number of crystallites, which strengthens the hydrogel network, restricting the diffusion of curcumin from the hydrogel (Shefa et al., 2020). Host-guest interactions are another method of incorporating curcumin in polymers. Inclusion complexes form between curcumin and host molecules like cyclodextrins (Tang et al., 2002). Cyclodextrins provide a hydrophobic cavity for curcumin and a hydrophilic exterior that helps in solubility (Yadav et al., 2009). A study by Nikolić et al. (2023) fabricated a thermosensitive poly (N-isopropyl acrylamide/sodium alginate) hydrogel using cyclodextrin. The use of host-guest interaction cross-linking method can achieve precise and controlled drug release, which is important in modulating immune responses over time and minimizing acute immune response (Geng et al., 2024). Physical cross-linking is a good method of fabricating curcumin hydrogels as it does not use toxic reagents, which is safer and biocompatible (Qureshi et al., 2020). Moreover, hydrogels using a physical cross-linking method are reversible based on their response to pH, temperature, and ionic strength (Bustamante-Torres et al., 2021). Although effective, physical cross-linkers produce hydrogels with weaker mechanical strength, which may affect the efficiency of encapsulation of curcumin in the hydrogel (Taaca et al., 2022).

Simple diffusion/partitioning is another method that is used to overcome the insolubility of curcumin, which does not require covalent bonding. Curcumin diffuses into the hydrogel mesh or partitions into micelles, liposomes, or other nanocarriers embedded within the hydrogel network. The use of simple diffusion is observed in a study that investigates curcumin-loaded micelle hydrogel. The curcumin is encapsulated in polymeric micelles that are embedded in a PEG-PCL copolymer using a one-step solid dispersion method. This method allows prolonged release of curcumin for wound repair (Gong et al., 2013). Apart from that, a similar study loaded curcumin in micelles formed by Pluronic F127-benzaldehyde (PF127-CHO). The hydrogel was cross-linked via a reversible Schiff’s base reaction that creates a pH-responsive release of curcumin for sustained release of curcumin (Sadeghi-Abandansari et al., 2021). The encapsulation of curcumin was also done by loading curcumin in liposomes embedded into a lysine-collagen hydrogel. This is effective in surgical wound healing due to the hydrogel’s ability to retain curcumin in the liposome core (Cardoso-Daodu et al., 2022). The method of simple diffusion leads to a burst release of curcumin, providing a rapid anti-inflammatory effect. While it is beneficial for immediate immune response, the less controlled release of curcumin may cause localized immune activation and unpredictable immune response (Huang and Brazel, 2001).

The cross-linking of hydrogels should be carefully considered, as it creates the 3D network structure that connects the polymer chains to form a semi-solid material. The cross-linking affects the hydrogel’s mechanical properties, elasticity, tensile strength, stability, and ability to absorb water (Bhattacharjee and Ahearne, 2021). Apart from mechanical properties, the degree of cross-linking of the hydrogel also influences the immune response. Factors such as the degree of cross-linking, the type of polymer, and the cross-linking agent that is used can induce an immune response. In a study based on polymeric micelles, micelles that were cross-linked with a lower cross-linking density influenced the immune response by enhancing the release of inflammatory cytokines while promoting an immunomodulatory effect in monocytes. A higher cross-linking density was crucial to minimize the activation of the innate immune system and monocyte uptake without affecting the lysis or aggregation of red blood cells (Gardey et al., 2020). A higher degree of cross-linking potentially triggers the immune response more due to more foreign body recognition by the immune cells (Butenko et al., 2024). Thus, the degree of cross-linking must be carefully considered. A similar study observed the effect of neutrophils on collagen scaffold cross-linking agents. The study recorded that different cross-linkers have different effects on the inflammatory micro-environment and the production of neutrophils. Certain cross-linkers can induce an inflammatory response, while others can induce an anti-inflammatory response (Ye et al., 2010, Ma et al., 2014).

The figure illustrates different cross-linking methods to ensure the successful encapsulation of curcumin hydrogels. The cross-linking methods include ionic interactions and hydrogen bonding, covalent interactions, host-guest interaction, and simple diffusion.

6. Mechanical and Physiochemical Properties of Curcumin Hydrogel & Immune Response

The mechanical properties of the hydrogel are an important aspect that is carefully considered and tailored according to its functionality and use. The addition of curcumin not only serves a therapeutic purpose but also enhances the hydrogel’s mechanical properties, particularly in terms of strength and elasticity (Feng et al., 2021, D et al., 2016). The strong mechanical properties are achieved due to the role of curcumin, which can act as a cross-linker, creating stronger bonds between the polymer chains in the hydrogel (D et al., 2016). Apart from improving mechanical properties, curcumin also improves the pore size of hydrogels. Curcumin significantly improved the pore sizes of hydrogels when hydrogels were formed using the gas-foamed method (Udeni Gunathilake et al., 2017). However, in curcumin hydrogels, the pores obtained were less regular, indicating the pores are filled with curcumin (Khaleghi et al., 2023, Sun et al., 2024).

The mechanical properties of hydrogels are important when used as therapeutics, as their physicochemical properties influence the immune response and the efficacy of the therapy. Factors such as the size of scaffolds, shape and topography, surface properties, charge, and stiffness of the biomaterials affect the immune response of the body. In terms of surface property, cells prefer highly hydrophilic surfaces compared to hydrophobic surfaces. Hydrogels are naturally hydrophilic, but the integration of curcumin into hydrogels may affect their hydrophilicity due to curcumin’s hydrophobic nature (Feng et al., 2021). The addition of functional groups such as Polyethylene glycol (PEG) can improve curcumin’s hydrophilic nature (Yakub et al., 2022). Hydrophilic surfaces decrease the adhesion of macrophages and monocytes while stimulating the apoptosis of adherent macrophages (Jones et al., 2007, Brodbeck et al., 2002). In hydrophilic surfaces, the macrophages stimulate anti-inflammatory properties that decrease inflammation (Visalakshan et al., 2019, Lv et al., 2018). However, on hydrophobic surfaces, adhesion of CD8T lymphocyte cells has been recorded in various studies (Chang et al., 2009). The hydrophobicity of the biomaterial is recognized as DAMPS by PPR in the innate immune system (Seong and Matzinger, 2004, Andorko and Jewell, 2017). Moreover, the macrophages differentiate into a pro-inflammatory phenotype when exposed to hydrophobic surfaces (Moyano et al., 2016, Visalakshan et al., 2019, Lv et al., 2018). Thus, proving that the hydrophobicity and hydrophilicity of biomaterials have a significant effect on the immune response.

Apart from hydrophobicity and hydrophilicity, surface charge also affects the immune response. The addition of curcumin may affect the charge of the hydrogel, as the charge of curcumin differs based on the pH. The higher the pH, the more negatively charged the curcumin is, creating a negatively charged hydrogel when encapsulated (Ternullo et al., 2019). Hydrogels that have negatively charged surfaces reduce the adhesion of monocytes while enhancing apoptosis levels (Brodbeck et al., 2002). Moreover, it is less efficiently internalized by antigen-presenting cells (APCs) and tends to suppress the immune response (Mariani et al., 2019). However, positively charged materials trigger the activation of NLRP3 inflammasome in the innate immune system (Neumann et al., 2014). The overall surface charge of the hydrogel can be manipulated based on the charge of the polymers incorporated. Besides charges, the smoothness or roughness of surfaces also triggers an immune response. A smooth surface does not promote cell adhesion, differentiation, and migration compared to rough surfaces (Tong and Derek, 2022). Rough surfaces that have elongated grooves allow macrophages to polarize into the M2 phenotype, while smooth surfaces with round morphology induce the macrophages to polarize into the M1 phenotype (Wilson, 2023)

Furthermore, the porosity of the biomaterial is an important factor that facilitates the migration and proliferation of cells (Murphy and O’Brien, 2010). Additionally, it significantly impacts the immune response by influencing cell-material interactions and modulating inflammatory reactions. The addition of curcumin has been recorded to improve porosity in many studies (Kossyvaki et al., 2022, Sood et al., 2023). A more porous scaffold supports the infiltration of macrophages while promoting regenerative responses. It has been suggested that larger pores promote the polarization of macrophages into the M2 phenotype, while smaller pores promote the polarization of macrophages into the M1 phenotype (Liu et al., 2020). The stiffness of biomaterials also affects the macrophages. Studies have revealed that increased stiffness increases the secretion of pro-inflammatory cytokines and affects the polarization of macrophages into the M1 phenotype (Chen et al., 2020, Sridharan et al., 2019).

Since porosity is a factor that affects the ability of hydrogels to absorb water, it is intrinsically connected to swelling behavior. Porosity and swelling rate are two factors that regulate the release kinetics of curcumin in hydrogel (Alven et al., 2020). Hydrogels with high porosity lead to high water uptake that drives swelling and enlarges the hydrogel size, thereby enhancing the diffusion rate for curcumin molecules (Orbay et al., 2023). Hydrogels with high porosity and swelling ratio exhibit faster release profiles, providing an initial burst of curcumin that may be beneficial in cases where rapid suppression of acute inflammation is required (Liu and Chen, 2024). Conversely, an ideal amount of porosity allows a controlled swelling that restricts rapid diffusion, leading to sustained release over extended periods, which is important for chronic inflammatory conditions (Lu et al., 2025). The sustained release of curcumin allows continuous downregulation of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β, and supports macrophage polarization towards the M2 phenotype (Hu et al., 2021). Biodegradability is another important physicochemical property that affects the curcumin release from hydrogels. The rate and mechanism of hydrogel degradation determine how quickly the polymer breaks down, allowing diffusion of curcumin (Mndlovu et al., 2024, Udeni Gunathilake et al., 2017). Hydrogels that degrade faster allow a more rapid release of curcumin, while slower degradation promotes sustained and controlled drug delivery over an extended period (Zhang et al., 2025). The biodegradation profile also influences immune response, with rapid degradation triggering local inflammatory reactions due to polymer byproducts, while gradual degradation ensures minimal immune activation (Tsung et al., 2023). Table 3 provides a systematic description of the effect of mechanical and physiochemical properties on curcumin release kinetics and immune response.

These findings prove that these factors have a significant effect on immune responses. In general, understanding these effects can significantly improve the therapeutic potential of the biomaterial. It can be concluded that fabrication techniques influence the hydrogel’s mechanical properties, affecting the immune response and its therapeutic potential.

7. Current Limitations of Curcumin Hydrogel

Although curcumin hydrogels have tremendous potential in ameliorating various inflammatory-related diseases and injuries (in vivo & in vitro), significant issues still hinder their use in clinical settings. A common limitation of curcumin hydrogel is the scalability and reproducibility of these formulations to ensure uniform loading of curcumin, cross-linking of hydrogel, and physiochemical stability across large-scale batches can be technically demanding. The standardization of the quality of curcumin is also a major concern, as the therapeutic potential might differ based on the batch of curcumin powder produced and the part of the rhizome of the turmeric plant from which curcumin is obtained (Thakur et al., 2022, Hsu et al., 2023).

Furthermore, hydrogels are very sensitive to sterilization due to the presence of water. Common sterilization techniques include steam heat from autoclaving, gamma or electron beam irradiation, ethylene oxide gas, or chemical disinfection using ethanol (S.A. Bento et al., 2023). Aseptic techniques involving heat and radiation have the potential to degrade the polymer structure that may compromise its physicochemical and mechanical properties (Korolev et al., 2021; Azevedo et al., 2025). The incorporation of curcumin makes it even harder for sterilization as curcumin is sensitive to UV degradation and degrades at high heat and releases toxic byproducts (Wang et al., 2019, Masih and Iqbal, 2022). Thus, most of the time, the hydrogels are dried before sterilization and rehydrated before application, but this sterilization method is not ideal for certain applications and polymers (S.A. Bento et al., 2023).

Although curcumin is considered GRAS, the combination of a natural compound with an advanced biomaterial may introduce additional complexity (Islam et al., 2024). A comprehensive biocompatibility and toxicological test must be done to further confirm the safety and efficacy of curcumin hydrogel (Fu et al., 2024). Moreover, the long-term safety profile of curcumin hydrogel remains insufficiently characterized, such as unpredictable degradation byproducts, systemic absorption following prolonged release, and the stability of the curcumin within the human physiological microenvironment (Alberts et al., 2025). It is important to note that although curcumin is safe, certain people might react differently and trigger an immune response when exposed to curcumin (Hewlings and Kalman, 2017). Future studies should therefore emphasize a standardized fabrication protocol, ensure rigorous preclinical evaluation, and comply with necessary regulatory requirements to address this limitation and accelerate clinical translation.

8. Conclusion & Technical Recommendations (Future Prospect)

To optimize the fabrication of curcumin hydrogels as a potential for therapeutics in various diseases, several key factors should be considered. In biomaterials, material selection is an important factor that should be considered. Materials should be biocompatible polymers such as chitosan, gelatine, or alginate, which are excellent materials that mimic the ECM and their ability to support the therapeutic action of curcumin while maintaining structural integrity. The materials should promote cellular adhesion and enhance tissue regeneration while modulating the immune response to create a microenvironment ideal for inflammation resolution (Boso et al., 2020).

Curcumin’s poor solubility and bioavailability present challenges that can be addressed through strategic formulation. Adding cyclodextrins and PEG significantly improves the solubility of curcumin and its bioavailability, further improving its anti-inflammatory efficacy (Yadav et al., 2009). Furthermore, fabrication strategies to improve the drug delivery of curcumin are important. Curcumin-loaded nanoparticles or micellar systems significantly improve the stability of the drug and ensure targeted action at the site of inflammation. This method protects the curcumin from degradation, improves solubility, and enhances bioavailability (Liu et al., 2023). This drug delivery system should be designed to ensure burst release of curcumin (to combat acute inflammation via the rapid suppression of pro-inflammatory cytokines) followed by sustained release (to manage chronic inflammation and long-term immunomodulation).

Factors such as mechanical strength, swelling behavior, and sustained drug release should be carefully tailored by optimizing the composition of the hydrogel and cross-linking agents used. Curcumin hydrogels can further be improved in areas such as biocompatibility, controlled release of curcumin, and immune modulation by fabricating them to exhibit responsive properties such as thermos-sensitivity or pH-sensitivity that allow the controlled rate of drug delivery (Gupta et al., 2002). Developing smart and responsive hydrogels allows better control over curcumin release to ensure continuous anti-inflammatory effects. Furthermore, the curcumin hydrogel can incorporate materials like gold or Ag NPs to improve the stability of curcumin and therapeutic efficacy (Salama et al., 2024).

Innovative fabrication technologies such as 3D bioprinting could be studied. 3D bioprinting allows controlled spatial distribution of curcumin within the hydrogel scaffold. The hydrogel can ensure precise delivery of curcumin to the targeted area (Xia et al., 2022). Recent advances in hydrogel fabrication have introduced 3D bioprinting as a powerful tool to deliver curcumin more effectively. Studies have recorded the use of printable bioinks made from gelatin methacryloyl (GelMA) and curcumin for wound healing (Xia et al., 2022). Other studies also recorded the use of 3D bioprinting in the fabrication of curcumin-loaded cellulose esters-based particles and alginate hydrogel as living tissue models that release curcumin as a drug (Carvalho et al., 2023). The use of a 3D bioprinting system allows precise spatial placement, tunable release kinetic profile, and prolonged retention of curcumin that aids in its low solubility and rapid degradation (Zhou et al., 2024, Carvalho et al., 2023). Nonetheless, during the 3D bioprinting process, cells undergo an immense amount of stress, thus making it harder to maintain high cell viability when extruded out of the system. Achieving good rheological properties while maintaining cell viability is a challenge (Gogoi et al., 2024).

Beyond curcumin alone, hydrogels can be developed with immunomodulatory agents such as anti-inflammatory cytokines (IL-10, TGF-β) to modulate immune response and support tissue regeneration (Xiong et al., 2023). Incorporating mesenchymal stem cells and their extracellular vesicles could also improve their immunomodulatory properties in inflammatory-related diseases and injuries (Farahzadi et al., 2024).

Future technologies may include hydrogels incorporated with biosensors or fluorescent markers to track the efficacy of the treatment and ensure the regulation of the immune response through real-time monitoring systems (Völlmecke et al., 2022)These smart hydrogels can be engineered from conductive materials such as polymers, carbon or metallic nanofillers that can be printed into mesh electrodes inside drug-loaded matrices (Gamboa et al., 2023). These systems can report changes in strain, pH, redox state, enzymatic activity, or even curcumin release via the change of electrochemical and impedance readings (Mondal et al., 2024). In addition, hydrogels can be functionalized with sensing materials that can detect various stimuli such as differences in pressure, chemicals, pH, and biomolecules (Sun et al., 2021). By linking these sensor-based readouts with the drug release mechanism, curcumin hydrogels could be designed to modulate release in response to inflammatory markers, offering a personalized therapeutic approach.

Apart from sensor-based hydrogels, smart responsive hydrogels are also an emerging innovation that includes thermosensitive factors, enzymes, glucose, ROS or pH-sensitive systems that can control the release rate of curcumin. In terms of chronic wounds, factors such as pH imbalance and the accumulation of ROS and dysregulated enzyme activity can trigger a response for the hydrogel to release curcumin as the therapeutic agent in a controlled manner to regulate the wound microenvironment (Jia et al., 2023). A study recorded the used of DNA-based hydrogel that is responsive to ROS, which is often elevated in injured tissues. The hydrogel reduced inflammation and promoted antibacterial effects (Ye et al., 2025). Apart from pH and ROS-sensitive systems, temperature-responsive hydrogels are also widely studied due to their reversible sol-to-gel transition that depends on temperature change. Commonly used thermosensitive materials are poloxamers that are liquid at low temperatures but form micelles and induce gelation at higher temperatures. Thermo-sensitive hydrogels are commonly applied at body temperature to allow sustained drug release for tissue engineering applications (Guo et al., 2025). These technical recommendations and future directions can be emulated for further research on curcumin hydrogel to improve its therapeutic potential. Fig. 4 schematically represents the technical recommendation and future prospects.

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Fig. 4.

Technical recommendations and future prospects.

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The figure illustrates different technical recommendations and future prospects for improving the efficacy and fabrication of curcumin hydrogel. It includes suggestions such as the importance of material selection, increasing the bioavailability and solubility of curcumin, smart hydrogel innovations, and innovative fabrication techniques such as 3D bioprinting, fabrication with MSCs, EVs, anti-inflammatory cytokines, and biosensor-embedded hydrogel.

Curcumin, despite having remarkable anti-inflammatory and antioxidant properties, faces significant challenges such as solubility, stability, bioavailability, and effective delivery. Alternative solutions such as hydrogels and advanced biomaterials have demonstrated significant potential to overcome these limitations. Hydrogels provide a versatile platform for controlled and localized release while integrating curcumin as nanoparticles and micelles that enhance its therapeutic efficacy. The noteworthy evidence of curcumin hydrogel in modulating inflammation positions itself as a promising biomaterial for future research, paving the way for improved patient outcomes and innovative therapeutic potentials. Addressing and managing inflammation might just be the cure we all need for ameliorating the various inflammatory-related diseases.