Mussel-inspired adhesive hydrogels for local immunomodulation

Chaoming Xie *^abc, Yazhen Li *^d, Xiaochuan Guo ^e, Yonghui Ding ^f, Xiong Lu ^a and Shuquan Rao *^bc
aKey Laboratory of Advanced Technologies of Materials, Ministry of Education, Haihe Laboratory of Cell Ecosystem, Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University, Chengdu 610031, Sichuan, China. E-mail: xie@swjtu.edu.cn
^bState Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China. E-mail: raoshuquan@ihcams.ac.cn
^cTianjin Institutes of Health Science, Tianjin 301600, China
^dDepartment of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai 200125, China. E-mail: liyazhenqd@163.com
^eThe Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Southwest Jiaotong University, Chengdu, Sichuan 610031, China
^fCenter for Advanced Regenerative Engineering, Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA

First published on 13th January 2023

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Chaoming Xie

Chaoming Xie is a Professor in College of Medicine, Southwest Jiaotong University. He received his PhD degree in Materials Science from Southwest Jiaotong University in 2016 and then joined the Max Planck Institute for Polymer Research as a postdoctoral fellow (2016–2018). His current research interests are focused on polyphenol-based biomaterials for tissue regeneration.

Yazhen Li

Yazhen Li is a lecturer at the National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. He received his PhD degree in Stomatology from Sichuan University in 2022. His current research focuses on the applications of immunomodulatory adhesive hydrogels in tissue engineering.

Xiaochuan Guo

Xiaochuan Guo is an attending physician in the Third People's Hospital of Chengdu, Department of Rehabilitation Medicine. He received his PhD degree from Guangzhou University of Traditional Chinese Medicine. He is a youth member of the Brain Function Detection and Regulation Rehabilitation Committee of China Rehabilitation Medical Association. His research focuses on neurological and cardiac rehabilitation by combining acupuncture and biomaterials.

Yonghui Ding

Yonghui Ding is currently a research assistant professor at the Center for Advanced Regenerative Engineering (CARE) and Department of Biomedical Engineering at Northwestern University. He received his PhD degree in Mechanical Engineering from The Hong Kong University of Science and Technology in 2014 and then joined the University of Colorado, Boulder as a postdoctoral fellow (2015–2019). His research focuses on the design and manufacturing of advanced biomaterials for tissue regeneration.

Xiong Lu

Xiong Lu is a Professor of College of Medicine, Southwest Jiaotong University of China. He received his PhD degree in the Department of Mechanical Engineering at Hong Kong University of Science and Technology in 2004. His research interesting is in the area of biomaterial surface engineering and soft materials for biomedical applications. Recently, he has been focusing on studying biomaterials based on Materials Genome Initiative to accelerate biomaterial development.

Shuquan Rao

Shuquan Rao is an Assistant Professor of Genetics, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College. The Rao laboratory uses human genetics to study hematopoiesis and how this process goes awry in human disease. To achieve this goal, he integrates modern human genetic studies with functional studies, employing a variety of innovative genomic technologies and traditional hematopoietic assays. He is also interested in the development of novel CRISPR/Cas editing tools and delivery platforms, designing improved therapies for a variety of genetic disorders.

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1. Introduction

The innate and adaptive immune systems are the main lines of defense that protect the body from pathogens and malignant cells.^1–4 Infection, trauma, tumors, and other factors can result in hypoactive or hyperactive immune activity.^5,6 To restore immune homeostasis for enhanced tissue regeneration or tumor eradication, there is growing interest in modulating the immune response. To achieve this, a large number of immunomodulatory biological agents have been developed, including cytokines, drugs, and peptides.^7–9 However, the systemic administration of these biologics is an untargeted approach with potential side effects. For example, systemic immunosuppression can alleviate the local symptoms of the disease, but it is associated with a lifetime of comorbidities due to weakening of the systemic immune system.^10,11 Checkpoint inhibitors can improve anti-tumor immunity but destroy homeostasis and immune tolerance and cause serious adverse events.^12–14 In addition, the targeting efficiency of agents is usually limited; thus, large doses of repeated administration are needed.^15,16 Therefore, encapsulating biologics through biomaterials or directly modulating local immune responses through biomaterials is a potential therapeutic approach.¹⁷

Nanomaterials and macroscale materials have been explored to address these problems.¹⁷ In tumor therapy, owing to the increased permeability of the tumor vascular system, nanoparticles can gather around the tumor.^18–20 However, it is difficult for most of the nanoparticles injected into the system to reach the expected target, and the nanoparticles injected locally are excreted quickly from the injection site owing to their small size.^18,21–23 Macroscale materials can effectively load immunomodulatory drugs that can be placed directly at the sites of interest.^24–26 Among them, hydrogels, a type of three-dimensional polymeric macroscale material with a high water content, have been extensively studied in tissue engineering owing to their mechanical and chemical similarity to biological tissues.^27–30

The design of the physical and chemical properties of hydrogels has significant flexibility, and hydrogels with various properties, such as injectability, conductivity, and responsiveness, have been developed.^31–33 The unique properties of hydrogels make them suitable for tissue-engineering applications. Although hydrogels have many useful characteristics and there have been many recent advances, the application of hydrogels in tissue engineering still faces challenges.³⁴ Owing to the complexity of the environment surrounding the wound and tumor sites, robust interfacial adhesion between hydrogels and tissues remains a formidable challenge.^35,36

As an improved hydrogel design, mussel-inspired hydrogels possess robust tissue-adhesive properties.^27,37,38 Researchers introduced catechol compounds into the hydrogel, which provided a large number of catechol groups for the hydrogel, thus closely binding to the tissue surface through π–π interactions, cation–π interactions, and hydrogen bonding.²⁷ After the catechol groups are oxidized to quinone groups, they can form covalent bonds with –NH₂ or –SH on the tissue surface, which greatly improves the tissue adhesion of the hydrogel.³⁹ Robust adhesion provides the hydrogel with a wound sealing and hemostatic ability, and prolongs the effective concentration time of the drug.^40,41 Moreover, catechol compounds affect the local immune response via their reactive oxygen species (ROS) scavenging capacity.⁴² In addition, the adhesion of biomaterials to cells can regulate cell behavior and activation of immune cells to varying degrees.^43,44

The formation and adhesion mechanisms of catechol-bonded hydrogels, as well as their role in tissue regeneration and tumor treatment, have been summarized.^28,45 However, previous reviews have paid little attention to the local immunomodulatory properties of catechol-functionalized hydrogels. In this review, the current progress in strategies for designing adhesive hydrogels is discussed. Subsequently, the rational molecular structure design of mussel-inspired adhesive hydrogels for robust tissue adhesiveness and their local immunomodulatory mechanisms are discussed. Furthermore, the local immunomodulatory effects of mussel-inspired adhesive hydrogels in wound healing, gastrointestinal diseases therapy, bone/cartilage healing, tumor therapy and other diseases are summarized (Fig. 1). Finally, a few anticipated challenges and prospects related to the development of mussel-inspired adhesive hydrogels are discussed.

2. Design of mussel-adhesive hydrogel

2.1 Mussel adhesion chemistry

In nature, soft organisms, such as marine mussels, can closely adhere to a variety of surfaces, including rocks, ships, and even other biological surfaces, by secreting mussel foot proteins (Mfps) in wet or humid environments.²⁷ At least 20 Mfps have been identified in adhesive plaques of several mussel species. These Mfps form adhesive plaques between the mussel basal filament and objects (Fig. 2a).^37,46–48 It has been confirmed that this adhesion phenomenon is caused by 3,4-dihydroxy-L-phenylalanine (DOPA) in Mfps. In particular, Mfp-3 and Mfp-5 contain a large number of catechol groups.^49,50 In alkaline seawater, DOPA readily undergoes auto-oxidation to form dopaquinone, which promotes cohesion. However, oxygen dissolved in seawater can cause the oxidation of DOPA and decrease the adhesion of Mfps. The main reason mussels can maintain long-term adhesion is the continuous secretion of reductive proteins (e.g. Mfp-6) to maintain a dynamic balance between DOPA and dopaquinone (Fig. 2b).⁵¹ Dynamic redox reactions contribute to the durable and dynamic adhesion of mussel proteins. In addition, the catechol group in DOPA can undergo a reversible complexation reaction with free metal ions in seawater to increase the adhesion strength; DOPA can also be combined with different surfaces through π–π interactions, cation–π interactions, and hydrogen bonding.^47,52–54 After DOPA is oxidized, the catechol group is converted into a quinone group, which can form a covalent bond with –NH₂, –SH, and histidyl group on the tissue surface (Fig. 2b).^55,56

2.2 The rational molecular-structure design of mussel-inspired adhesive hydrogels

Mussel-inspired adhesive hydrogels have been prepared using different catechol-derived compounds such as polydopamine (PDA), tannic acid (TA), epigallocatechin gallate (EGCG), and gallic acid (GA).²⁷ According to the different methods of introducing catechol-containing compounds, mussel-inspired adhesive hydrogels can be divided into the following three categories: catechol protein-based adhesive hydrogels, catechol-functionalized polymer-based adhesive hydrogels, and catechol-functionalized nanomaterial-based adhesive hydrogels.

2.3 Local immunomodulatory mechanism of mussel-inspired adhesive hydrogels

During the disease process, the host immune system recruits different types of immune cells, including macrophages, T cells, B cells, and dendritic cells (DCs), to exert anti-inflammatory, pro-repair, and anti-tumor functions.^11,73 In this review, we summarize the regulatory mechanisms of catechol-containing compounds and mussel-inspired hydrogels related to immunity. Current related studies mainly involve macrophages and T cells. Macrophages are the first line of defense against the host immune system. According to the type of activation, macrophages are mainly divided into M1 macrophages (pro-inflammatory) and M2 macrophages (anti-inflammatory and pro-healing).^74,75 Classical M1 macrophages exert pro-inflammatory effects by producing high levels of inflammatory factors, such as interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), and interleukin 1 beta (IL-1β). In contrast, M2 macrophages exhibit significant anti-inflammatory and pro-healing effects by secreting repair factors, such as transforming growth factor beta (TGF-β), arginase 1 (Arg-1), bone morphogenetic protein-2, and vascular endothelial growth factor (VEGF). The functional diversity of macrophages relies on their highly plastic phenotypes in response to microenvironmental signals.

Some evidence has shown that PDA plays an anti-inflammatory role through its ROS scavenging and antioxidant properties.^42,76 PDA is formed by self-polymerization of DA in an alkaline oxygen-containing environment, and its molecular-structure is similar to that of mussel adhesion proteins, retaining a large number of phenolic hydroxyl groups.⁵⁷ Excess lipopolysaccharide (LPS) at the disease site enhances citrate transport to the cytoplasm by increasing the mitochondrial citrate carrier expression. Its metabolite nicotinamide adenine dinucleotide phosphate (NADPH) is a substrate for ROS generation catalyzed by NADPH oxidases.⁷⁷ ROS can stabilize hypoxia inducible factor-1α (HIF1α), thereby promoting glycolysis. Enhanced glycolysis ensures a competitive bioenergetic state and strong energy for M1 macrophage polarization, and provides precursors for the production and secretion of pro-inflammatory cytokines.⁷⁸ Previous experiments by our team confirmed that based on the antioxidant capacity of PDA, intracellular ROS could be effectively scavenged, thereby inhibiting the activation of M1 macrophages (Fig. 6a).⁴² Another study by our team also confirmed that PDA effectively cleared ROS in macrophages, which reduced the expression of TNF-α and IL-6 (M1), thereby increasing fibroblast activity, protecting fibroblasts from apoptosis, and achieving orderly wound healing in diabetes (Fig. 6b).⁷⁹ Zheng et al. confirmed that PDA NPs inhibit HIF1α expression and promote the reprogramming of M1 to M2, which is consistent with our experimental results.⁸⁰ Additionally, PDA-based adhesion properties affect the cell-adhesiveness of macrophages, which promotes the interaction between macrophages and the extracellular matrix.⁸¹ This process is mainly regulated by integrins, which play key roles in cell adhesion, macrophage polarization, and podosome formation. Downstream of podosome formation is the Rho family of guanosine triphosphatases, which is reported to be involved in actin stress fibers (RhoA), filopodia (Cdc42), and lamellipodia (Rac1).⁸² This subsequently leads to cytoskeletal rearrangements that facilitate the cell spreading and activation of M2 macrophages (Fig. 6a).⁴² Moreover, ROS scavenging inhibits the RhoA signaling pathway, which is an underlying pathway for PDA-activated M2 macrophage polarization.⁸³ PDA can also endow materials with immune-evasive properties. Wang et al. developed a PDA-inspired conductive ultrasoft hydrogel.⁸⁴ The typical foreign body response (FBR) markers, T cells (CD3), macrophages (CD68), type I collagen (Col I), and α-smooth muscle actin (αSMA) around the hydrogel were stained with fluorescent dye after one and 14 days. The PDA hydrogel was found to be suitable for long-term implantation with immune-evasive behavior (Fig. 6c).

As an effective antioxidant, TA has attracted the attention of researchers because of its immunomodulatory function. For example, in 2017, Hubert et al. used a multilayer film formed by TA and nonionic poly(N-vinylpyrrolidone) (PVPON) to encapsulate pancreatic islets, providing an immune protective barrier to reduce T cell responses in diabetes.⁸⁵ In 2020, Hubert et al. experimentally demonstrated that transplantation of PVPON/TA-encapsulated islets was immunomodulatory because of the significant decrease in ROS, inflammatory chemokines, and CD8 T cell effector responses, and concomitant increases in M2 macrophage and DC phenotypes.⁸⁶ Similar to PDA, TA can also affect macrophage polarization by directly interacting with toll-like receptor 4 (TLR4), thereby inhibiting NF-κB pathway activation and M1 polarization by reducing p65 subunit nuclear translocation.^87,88 It has been reported that the reduction of nuclear p65 may promote the conversion of heterodimer p65/p50 into homodimer p50/p50, and the increased p50/p50 could assist in the transcriptional upregulation of IL-10, which promotes M2c macrophage polarization through the IL-10R/STAT3 signaling pathway.^89,90 He et al. reported that a TA/Mg²⁺ coating manipulated the adhesion and morphology of macrophages, inhibited M1 polarization, exerted an anti-inflammatory effect, and promoted M2 polarization.⁹¹ Dong et al. utilized TA to assemble red blood cells (RBCs) onto a Ti surface, conferring anti-biological contamination and immunomodulatory properties to the implants.⁹² In the Ti group, macrophages were pancake-shaped (typical M1 macrophage phenotype), whereas the Ti-pTA and Ti-pTA-RBC groups showed varying degrees of elongated cells (typical M2 macrophage phenotype). The gene expression results showed a similar trend. These results confirmed that TA can affect the adhesion and morphology of macrophages, thereby regulating their phenotype.

EGCG, a tea polyphenol, has been proven by many studies to have an immunomodulatory ability.^93–95 In a model of spinal cord injury, Urdzikova et al. found that EGCG effectively reduced the nuclear translocation of the p65 subunit (RelA) of the NF-κB dimer, thereby regulating the macrophage phenotype and expression of inflammatory factors.⁹⁶ EGCG treatment can reduce the severity of experimental autoimmune encephalomyelitis in the central nervous system and promote M2 polarization, which is also associated with the NF-κB and glycolytic signaling pathways.⁹⁷ Additionally, EGCG inhibits M1 polarization of microglia, a type of brain immune cell, through the IGF-1/IGF1R signaling pathway.⁹⁸ In the LPS-induced acute lung injury mouse model, EGCG enhanced the expression of KLF4 in mouse lungs and promoted polarization of macrophages towards the M2 phenotype.⁹⁹ In a nonalcoholic fatty liver disease model, M1 macrophages were decreased but M2 macrophages were increased.¹⁰⁰ Chu et al. reported that EGCG-modified collagen membranes may promote M2 macrophage recruitment through CC chemokine receptor 2 (CCR2) signaling, favoring M2 polarization.¹⁰¹ Interestingly, Yang et al. studied the protective effect of EGCG on asthma and found that EGCG mainly acted on the HIF-1/VEGFA pathway of macrophages and blocked M2 macrophage polarization, thereby protecting mice from allergic asthma and inflammatory responses induced by house dust mites.¹⁰² T cells are important target cells for EGCG. Aktas et al. reported that EGCG inhibits NF-κB signaling in human myelin-specific CD4⁺ T cells, limits brain inflammation, and reduces neuronal damage.¹⁰³ Wang et al. found that EGCG inhibited T-bet, PU.1, and RORγt in naive CD4⁺ T cells, hindering Th1, Th9, and Th17 differentiation and alleviating experimental autoimmune encephalomyelitis.¹⁰⁴

Quercetin, a dietary flavonoid derived from natural plants, has ROS scavenging capabilities due to its internal catechol group, 2,3-double bond, and hydroxyl substituent, which have been proven to limit M1 macrophage polarization and drive M2 macrophage polarization.^105,106 On the one hand, querceptin controls the polarization of M1 by reducing the expression of the P65 subunit to control the combination of inflammatory factors in the nucleus. On the other hand, the ability of quercetin to drive M2 macrophage polarization is derived from the activation of glutathione (GSH) activity and prompt nuclear translocation of STAT6. GA-inspired biomaterials have also been shown to affect macrophage phenotype (Fig. 6d).⁷⁶

These reports support the potential effects of catechol-containing compounds and mussel-inspired biomaterials on M1/M2 polarization and T cells. The functional groups, hydrophilicity, roughness, and surface energy of the biomaterial surface are also important factors that affect the macrophage and T cell phenotypes.^107–109 Tan et al. compared the effects of PDA, polynorepinephrine coating (pNE), and poly-levodopa coating (pLD) on the phenotype of macrophages and found that the functional groups on the coating surface were the major factors affecting the macrophage phenotype.¹¹⁰ Further research is needed on the mechanism of the potential effects of catechol compounds and mussel-inspired hydrogels on immune cells.

3. Mussel-inspired adhesive hydrogels for local immunomodulation

3.1 Mussel-inspired adhesive hydrogels for wound healing

Wound healing is a complex biological process, and successful healing relies on the coordinated interaction of multiple cells, cytokines, and growth factors, particularly immune-related cells.^111,112 However, in many cases, such as in severe burns and pathological conditions (e.g., diabetes), the normal healing process is hindered; therefore, intervention is necessary to promote wound healing.^113,114 As a skin adhesive, hydrogels can avoid complicated suture processes, inhibit bacteria, and stop bleeding to accelerate wound healing, and their sealing ability is better than that of traditional sutures.⁴⁵ Its closure ability is also better than that of the traditional sutures. Mussel-inspired hydrogels have unique advantages such as skin adhesion ability. It not only has an excellent adhesion ability to effectively reduce bleeding but also can improve the local microenvironment of the wound surface, thereby accelerating wound healing.²⁷ Strategies for modulating immune responses based on mussel-inspired hydrogels are promising avenues for facilitating the wound-healing process. Numerous studies have demonstrated that mussel-inspired hydrogels can control local immune responses by modulating immune cells, particularly macrophages.

In 2021, Tu et al. developed a PDA-modified GO hydrogel (GDFE) to modulate macrophages and promote diabetic wound healing (Fig. 7a).¹¹⁵ The GDFE hydrogel effectively stimulated macrophage polarization into the M2 phenotype and even M2c phenotype, which released angiogenic factors (PDGF and VEGF) through the paracrine pathway in the relatively early stage of healing. This is mainly attributed to the synergistic effects of GO and PDA. GO and PDA have abundant carboxyl, amino, and hydroxyl groups, which can affect cell differentiation and promote polarization of macrophages towards the M2 phenotype.

Li et al. developed an injectable adhesive hydrogel (HA-DA/MP) based on polydopamine (PDA) coated with Ti3C2 MXene, oxygenated hemoglobin (HbO₂), and hyaluronic acid grafted with dopamine (HA-DA) (Fig. 7b).³¹ HbO₂ not only acts as an oxygen carrier to controllably release oxygen when activated by the mild heat produced from near-infrared (NIR) irradiation, but also as a horseradish peroxidase to catalyze hydrogel formation. The stable photo-responsive heating behavior of MXene ensured repeatable oxygen release. During wound healing, the ratio of M2 macrophages (CD206) to M1 macrophages (CD86) was highest in the experimental group. Owing to the adhesion, ROS scavenging, antibacterial, immunomodulatory, and oxygen release abilities of the hydrogel, it greatly promotes cell proliferation, migration, and angiogenesis, and significantly promotes the healing of infected skin. Researchers confirmed that the ability of the hydrogel to modulate macrophage polarization was derived from HA-DA.

In 2022, Yuan et al. designed a photothermal hydrogel (HTHE-M@D) prepared using deferoxamine-loaded mesoporous PDA nanoparticles (M@D), tyramine-grafted human-like collagen (HLC-TA), and epigallocatechin gallate dimer-grafted hyaluronic acid (HA-EGCG).¹¹⁶ With the incorporation of M@D nanoparticles, HTHE-M@D hydrogels showed a larger adhesion strength (20.6 ± 0.6 kPa) than the control group (10.6 ± 0.5 kPa) and adhered firmly to the surface of the rat heart, liver, spleen, lung, and kidney. The increased adhesion was attributed to the interaction between the amino, imidazole, and mercaptan groups on the tissue surface and the catechol and polyphenol groups of the hydrogel. Cellular and diabetic foot ulcer rat experiments confirmed that the HTHE-M@D hydrogels allowed macrophages to maintain the M2 phenotype. Researchers explained that this behavior was mainly due to high-molecular-weight HA, which could facilitate M2 phenotype-specific gene expression and suppress M1 phenotype-specific gene expression. However, the PDA and EGCG in the hydrogel may also facilitate this effect.

In another study, based on the therapeutic effects of EGCG, Zhao et al. formed a multifunctional “smart” hydrogel (EACPA) by copolymerizing EGCG, 3-acrylamido phenylboronic acid (APBA), and acrylamide (Fig. 7c-i).¹¹⁷ Owing to the dynamic characteristics of the borate bond, the hydrogel had a moderate tissue adhesion ability and could be easily stripped from skin tissue without any residue (Fig. 7c-ii). Suitable adhesion and excellent tensile properties ensured the effective sealing effect of the hydrogel on the wound. In vitro cell experiments confirmed that the expression of M2 macrophage markers (CD163, CD206, and Arg1) was upregulated in the EACPA group. Using EACPA hydrogels as a dressing for chronic diabetic wounds significantly increased the expression level of TGF-β1 to 307.9 pg mg⁻¹, which was significantly higher than that in the untreated control group (158.6 pg mg⁻¹). TGF-β1 is an immunosuppressive factor that induces M2 polarization of macrophages to reduce inflammation. Moreover, a significant increase in F4/80⁺CD163⁺ macrophages (M2) was observed in the EACPA group (Fig. 7c-iii). Furthermore, EGCG released with control exerted antibacterial, antioxidant, pro-angiogenic, and anti-inflammatory effects, thereby promoting diabetic wound healing (Fig. 7c-iv). With the release of EGCG, the adhesion of the hydrogel gradually decreased, and the hydrogel could be easily removed after seven days of treatment, thus avoiding secondary damage to the wound site.

Some researchers have loaded immunomodulatory drugs into hydrogels to promote skin healing.^118,119 Lu et al. prepared a dual-responsive hydrogel drug delivery system based on polyacrylamide, catechol-chitosan, and acetalized cyclodextrin nanoparticles to release Resolvin E1, a specialized pro-resolving lipid mediator that can influence the transformation of the macrophage phenotype via changing the leukotriene ratio.¹¹⁸ Sun et al. developed a new zinc alginate hydrogel embedded with hollow dopamine nanoparticles loaded with the potent pro-healing peptide RL-QN15.¹¹⁹ The hydrogel stimulated the rapid aggregation of M1 macrophages in the relatively early stage of healing and induced the transition of macrophages to the M2 phenotype in the later stage of healing. This phenomenon may be related to the co-action of RL-QN15 and the hollow dopamine nanoparticles.

We prepared a temperature-responsive adhesive hydrogel (PGA-GelMA) by complexing polymerized gallic acid (PGA) with gelatin methacryloyl (GelMA) (Fig. 7d).⁷⁶ The hydrogel adhered to the warm rat skin after being pressed and did not fall off due to the deformation of the skin. After cooling the hydrogel using an ice bag, it separated automatically without any skin residue (Fig. 7d-i). In addition, the PGA-GelMA hydrogel exhibited anti-inflammatory and immunomodulatory properties (Fig. 7d-ii). Compared to macrophages treated with the GelMA hydrogel, the expression levels of iNOS, IL-6, and TNF-α in macrophages treated with the PGA-GelMA hydrogel were significantly reduced. At the same time, the expression levels of IL-10, Arg1, and CD206 in macrophages treated with the PGA-GelMA hydrogel increased, effectively converting macrophages into anti-inflammatory phenotypes. The PGA-GelMA hydrogel was further used as a treatment patch for full-thickness skin defects in patients with diabetes. The number of CD206 positive M2 macrophages in the subcutaneous layer of the wound site was higher, which confirmed that the PGA-GelMA hydrogel activated macrophage polarization, thus regulating the wound microenvironment to promote wound healing (Fig. 7d-iii).

In conclusion, a number of studies have confirmed the regulatory effect of mussel-inspired adhesive hydrogels on a macrophage phenotype, whereby they induce the secretion of anti-inflammatory cytokines and reparative growth factors (i.e., VEGF and epidermal growth factor (EGF)) for neovascularization and tissue regeneration.^31,115–117 However, current studies have paid little attention to the mechanism of hydrogel regulation of macrophages and other immune cells, and there is a lack of research on the relationship between adhesion and the local immune microenvironment. Resolving these issues is equally important for understanding the regulation of the local microenvironment and the wound healing process.

3.2 Mussel-inspired adhesive hydrogels for gastrointestinal diseases therapy

Due to the continuous secretion of digestive fluid and gastrointestinal movement in the gastrointestinal cavity, the internal environment in the gastrointestinal cavity is relatively complex, limiting the applications of adhesive hydrogels.¹²⁰ The prolongation of the gel time and the lack of adhesion to the target position may affect the therapeutic effect.¹²¹ Therefore, it is very important to develop the hydrogels with strong in-situ wet adhesion in complex and harsh environments.¹²² The mussel-inspired hydrogels could gel quickly in a few minutes under alkaline conditions, and show strong adhesion to the tissue surface.¹²³ For example, Shin et al. formed the HA–catechol hydrogel by oxidative crosslinking of HA functionalized with an adhesive catecholamine motif of Mfp.¹²³ The adhesion of the hydrogel made it easy to apply to the surface of tissue (liver and heart), even in wet or beating states. However, when phenolic hydroxyl groups are exposed to oxidants such as oxygen, phenolic hydroxyl groups are oxidized to quinone groups, resulting in loss of adhesion.⁴⁹ In order to rescue the loss of adhesion of mussel-inspired hydrogels, Bian and Chiu et al. prepared a bioadhesive hydrogel (HACN) based on thiourea–catechol reaction inspired by the thiol-rich mfp-6.¹²⁴ The existence of reductive thiourea groups helped to reduce the over-oxidation of catechol groups, thus maintaining the adhesion of hydrogels. The HACN hydrogel could be delivered to the ulcer site in a pig stomach through an endoscope and be quickly gelled in an acid environment. In animal models, the hydrogel accelerated ulcer healing by inhibiting inflammation, angiogenesis and promoting re-epithelization, providing a feasible and effective method for the treatment of gastric ulcer. In another study, Bian and Chiu et al. added a second hydrogel network of 4-arm thiolated polyethylene glycol (PEG) on the basis of HACN hydrogel, which reinforced the HACN hydrogel network through thiol–catechol reaction (Fig. 8a).¹²⁵ The experimental results showed that the complex hydrogel adhered to the upper gastrointestinal bleeding wound of pigs for 48 hours, which proved its broad application prospect in gastrointestinal hemostasis.

Patients with colorectal cancer, Crohn's disease, and intestinal ischemia usually require surgery.^126,127 Generally, surgery to treat these diseases requires removing or bypassing the diseased tissue and suturing the two segments of the normal tissue. One of the most fatal complications of surgery is postoperative anastomotic leakage (PAL), which not only affects postoperative recovery but also increases the risk of death.^128,129 Researchers have been trying to develop biomaterials that can adhere to the surface of intestinal tissue to accelerate healing. To restore PAL, a mucoadhesive hydrogel sealant based on acrylamide, methyl acrylate, acrylic acid, and bis-acrylamide was developed, which can be grafted onto the intestinal tissue via a mutually interpenetrating network that traverses the tissue and hydrogel patch simultaneously.¹³⁰ The experimental results showed that the hydrogel not only achieved an ideal sealing effect but also maintained adhesion for a long time in a complex internal environment. Joo and co-workers developed a fibrous membrane sealing patch using polycaprolactone (PCL), gelatin, and electrospinning technology.¹³¹ The results showed that when the ratio of PCL to gelatin was 1:4, the wound healing effect was the best. It has potential applications as a material for repairing postoperative leak-proof tissue.

Inspired by mussels and barnacles, Huang et al. developed a novel dopamine-conjugated xanthan gum (Da-g-Xan) hydrogel adhesive, in which xanthan gum acted as a “structure-based adhesion component” of barnacles and dopamine as a “molecule-based adhesion component” of mussels (Fig. 8b-i).¹³² The adhesion strength of the Da-g-Xan hydrogel to pigskin reached 27 kPa, exceeding the adhesion strength of commercial fibrin gels. With the degradation of the hydrogel, the released Da-g-Xan could specifically bind to the CD206 of macrophages and mediate M2 macrophage polarization through increasing the phosphorylation of extracellular regulated protein kinase (ERK). Activated M2 macrophages then enhanced the migration, proliferation, and collagen synthesis of fibroblasts via the paracrine pathway (Fig. 8b-ii). Finally, the hydrogel showed a good therapeutic effect in a colonic anastomotic model.

In 2021, Wang et al. designed a dihydrocaffeic acid-modified poloxamer (P-DA) hydrogel to improve the therapeutic effect on injured colons (Fig. 8c).¹³³ The failure force, adhesion work, and adhesive force of the P-DA hydrogel were significantly larger than those of the poloxamer 407 hydrogel. Moreover, the adhesion ability of the P-DA hydrogels increased with increasing DA content, indicating that the adhesion ability of the P-DA hydrogels was largely attributed to DA. After treating 2,4,6-trinitrobenzenesulfonic acid-induced ulcerative colitis with EGF-loaded P-DA hydrogels, significant increases in CD68⁺CD163⁺ macrophages (M2) and obvious decreases in CD80⁺ macrophages (M1) were observed in the P-DA-EGF and P-EGF hydrogel groups. Researchers have attributed this phenomenon to the EGF. However, according to the experimental results, compared with the P-EGF groups, obvious increases in M2-typed macrophages were observed after P-DA-EGF hydrogel treatment, indicating that DA also played a role in the polarization of macrophages.

In 2022, Wu et al. prepared an injectable asymmetric adhesive hydrogel based on ultraviolet-curable catechol-grafted hyaluronic acid (HAD) (Fig. 8d-i).¹³⁴In situ injected HAD precursors adhered well to the surfaces of different organs and materials, including polytetrafluoroethylene; therefore, the hydrogel was used as a wet adhesive for the injured cecum. After photocrosslinking, the outer surface of HAD showed antiadhesive properties, which could prevent the formation of postoperative adhesions after minimally invasive surgery (Fig. 8d-ii). HAD not only promoted M2 macrophage polarization but also potentially kept the wound in a steady state of remodeling with anti-inflammatory effects. The HAD formulation, as a polyanionic trap, effectively inhibited the aggregation of GATA6⁺ cavity macrophages that promote collagen deposition and abdominal adhesion, thereby preventing postoperative adhesion (Fig. 8d-iii).

Therefore, mussel-inspired adhesive hydrogels act as potential biomaterials for applications in gastrointestinal diseases, which can not only seal gastrointestinal wounds but also regulate the local immune microenvironment to promote healing. The performance requirements of hydrogels for gastrointestinal diseases are similar to those of hydrogels for skin wounds, such as wet adhesion and immunomodulatory properties; however, they also have different performance requirements, such as antiadhesive properties and stronger wet adhesion. Despite current progress, wet adhesion of gastrointestinal tract surfaces in a complex internal environment remains a great challenge.

3.3 Mussel-inspired adhesive hydrogels for bone/cartilage healing

Biomaterial-based tissue engineering technologies are rapidly developing. When implanted, the protein layer and complement factors are adsorbed on the surface of the material and recruit neutrophils and monocytes, which then differentiate into macrophages to promote an immune response.^135,136 The macrophages around the material regard the material as a foreign body, resulting in FBR, accompanied by excessive inflammation and fibrosis, affecting the healing speed of bone/cartilage.¹³⁷ The traditional design theory focuses on the construction of bioinert materials to reduce the immune response. However, immune cells and cytokines are required for bone/cartilage regeneration. Therefore, more material design strategies have shifted from 'immune-evasive' biomaterials to 'reprogramming' ones.^138,139 This strategy aims to regulate the local immune environment using biomaterials to accelerate the speed and quality of tissue healing. Delivering cytokines and bioactive molecules and regulating surface topography, architecture, wettability, and surface charge are commonly used methods for bone/cartilage immunoregulation. For example, Zhu et al. customized honeycomb structures of different scales on titanium surfaces to explore their effects on macrophage phenotypes and immunomodulatory effects on osteogenesis.⁸² The results showed that the expression of CD206, IL-4, and IL-10 was the highest in the 90 nm sample group, which significantly activated M2 polarization of macrophages. The results of high-throughput sequencing in the transcriptional group showed that the immunomodulatory effect was related to the activation of the RhoA/Rho-associated protein kinase signaling pathway. Hamlet et al. compared the effects of hydrophilic-modified micro-rough (modSLA) and micro-rough (SLA) Ti discs on macrophage polarization.¹⁴⁰ The experimental results showed that in the modSLA group, the expression of CD163 and Arg1 was higher, M2 polarization of macrophages was observed, and the osteogenic effect was stronger. In contrast, in the SLA-Ti group, the expression of inflammatory cytokines was upregulated and osteogenic-related gene expression was not observed. The increase in hydrophilicity was confirmed to be beneficial for the M2 polarization of macrophages. In addition, it has been reported that divalent cations, Ca²⁺ and Sr²⁺, can increase the expression of Arg1, CD163, and TGF-β1, thus enhancing osteogenic differentiation.¹⁴¹ Sang et al. constructed a thermosensitive injectable hydrogel loaded with primary chondrocyte-derived exosomes to promote cartilage repair based on Pluronic Fmur127 and hyaluronic acid, which effectively increased the number of CD163⁺ cells (M2) in the cartilage and synovium.¹⁴²

We constructed a cartilage extracellular matrix-like hydrogel scaffold (Col/PDA/HA) based on collagen (Col) and PDA-modified HA complexes (Fig. 9a-i).¹⁴³ The Col/PDA and Col/PDA/HA hydrogel scaffolds exhibited better cell adhesion properties than the Col and Col/HA hydrogels because of the interaction of the catechol groups within the hydrogel scaffold with the amine and thiol functional groups on the cell membrane (Fig. 9a-ii). The experimental results confirmed that the Col/PDA/HA hydrogel scaffold provided a pro-chondrogenic immune microenvironment via effective anti-inflammatory effects and promoting macrophage polarization to the M2 phenotype, which may be mainly attributed to the synergistic effect of PDA and HA (Fig. 9a-iii). In another study by our team, PDA-mediated hydroxyapatite nanoparticles (PHA) and graphene oxide (PGO) were mixed into an alginate/gelatin (AG) solution to synthesize a conductive hydrogel scaffold (PGO-PHA-AG) for periodontal bone regeneration in diabetes (Fig. 9b-i).⁴² Owing to the cellular affinity of the catechol groups and wrinkled structure of PGO, the PGO-PHA-AG hydrogel scaffold exhibited excellent cell adhesion properties (Fig. 9b-ii). Furthermore, the PGO-PHA-AG hydrogel scaffold was proven to have the ability to regulate macrophage polarization both in vitro and in vivo (Fig. 9b-ii). These studies have reported encouraging results. However, the topography, structure, wettability, and surface charge effects of mussel-inspired hydrogels on the immune process need further research, which will be helpful for developing functional biomaterials for application in bone/cartilage tissue engineering.

3.4 Mussel-inspired adhesive hydrogels for tumor therapy

Tumors are among the most life-threatening diseases worldwide. With aging and changes in the living environment, tumor incidence is increasing annually.¹⁴⁴ Currently, the most commonly used clinical treatment methods for tumors include surgery, radiotherapy, and chemotherapy.^145,146 Chemotherapy plays an important role in tumor treatment, but the toxic effects of chemotherapeutic drugs on normal cells often cause side effects, such as hair loss, fatigue, and even life-threatening side effects.^147,148 Recently, immunotherapy has received extensive attention, and significant progress has been made in the field of anti-tumor therapy.^149,150 Immunotherapy can enhance the targeting effect of immune cells on tumor cells and inhibit tumor immune escape, thereby enhancing the effectiveness of anti-tumor treatment. Owing to the limitations of chemotherapy drugs, immunotherapies based on biomaterials or biomaterials delivering immune agents have received increasing attention.

Many studies have confirmed the potential application of catechol compounds in anti-tumor therapy.^151–153 Catechol compounds are usually combined with other treatment methods, such as photosynthesis and radiology, which provides great advantages for tumor treatment.^151,154 PDA nanoparticles can be used as photothermal therapy platforms for tumor treatment because of their strong NIR absorption and high photothermal energy conversion efficiency.¹⁵¹ The catechol group on its surface can chelate anti-tumor drugs on the surface of nanoparticles, thus achieving synergistic effects of photothermal therapy and chemotherapy. Huang et al. synthesized nanoparticles (PLGA-pTA NPs) for photothermal immunotherapy using pTA coated with PLGA.¹⁵² PLGA-pTA NPs exhibited excellent photothermal conversion efficiency. Moreover, after NIR irradiation, PLGA-pTA induced immunogenic cell death and promoted the maturation of DCs, thus inhibiting tumor growth and lung metastasis. After loading the anti-PD-L1 antibody, the tumor growth and metastasis were almost completely eradicated. These results confirmed that PLGA-pTA NPs could be used as a platform for delivering antineoplastic drugs combined with photothermal immunotherapy to effectively eliminate tumors.

Hydrogels have inherent advantages in anti-tumor research, including tissue regeneration, nanoparticle loading, and drug delivery. In particular, hydrogels formed in situ can be crosslinked to fill irregular areas by stimulating an external environment (temperature, pH, light, etc.).^155,156 An in situ hydrogel system based on methacrylated silk fibroin (SF) and chlorine e6 was used to treat tumors and repair wounds (Fig. 10a).¹⁵⁵ Under NIR irradiation, the hydrogel recruited tumor-associated macrophages (TAM) promoted the M1 polarization of TAM through the NF-κB signaling pathway, and promoted cytotoxic T cell activation to enhance anti-tumor therapy. The hydrogel system achieved a controllable anti-tumor response through NIR irradiation, providing a new platform for the treatment of melanomas.

Compared to other hydrogels, mussel-inspired hydrogels possess unique advantages such as better biocompatibility, bioadhesive ability, and immunoregulatory capacity.⁷⁶ Therefore, anti-tumor immunotherapy based on mussel-inspired hydrogels has attracted the attention of researchers. This type of hydrogel is usually loaded with catechol-modified nanoparticles, which have excellent therapeutic effects when combined with traditional treatment methods (phototherapy, radiotherapy, and surgery).^156,157 In 2021, Fan et al. developed an MnO₂-loaded injectable adhesive hydrogel based on catechol groups (Fig. 10b).¹⁵⁶ Mass tumor-derived protein antigens released after photothermal therapy adhered to the hydrogel, acting as an “antigen reservoir”. As a result, more immature DCs were recruited to the tumor site and more antigens were transferred to the nearby lymph nodes by DCs to stimulate the production of more effector T cells and memory T cells, thus further enhancing the anti-tumor immune response.

In 2022, our team developed a bioadhesive injectable hydrogel based on phenolic carbon quantum dot-supported Pd single atom nanozymes (DA-CQD@Pd SAN) for local immunomodulation and catalytically enhanced immunotherapy of tumors (Fig. 10c-i).¹⁵⁷ The catechol groups of the DA-CQD@PD SAN, along with their oxidized products (quinone and semiquinone), formed a catechol-based catalytic system. The system and Pd single atom jointly catalyzed the degradation of peroxide/persulfide to generate free radicals (Fig. 10c-ii), which caused immunogenic cell death of tumor cells and generated tumor-associated antigens in tumor lysates, thus triggering anti-tumor immune responses. In addition, due to electronic metal support interactions, electrons were transferred from Pd to the quinone group of DA, forming a catechol-quinone redox pair, which endowed the hydrogel with a strong adhesion ability and enabled the hydrogel to stably and seamlessly encapsulate the tumor tissue (Fig. 10c-iii). Thus, the hydrogel acted as a local niche, providing continuous release of the immune adjuvant CpGODN to enhance anti-tumor immune responses, prevent systemic exposure, reduce the effects of CpGODN toxicity, and prevent its degradation. When combined with the checkpoint inhibitor anti-PD-L1, the hydrogel effectively induced adaptive anti-tumor immune responses, preventing tumor recurrence and metastasis. These results confirm that anti-tumor immunotherapy based on mussel-inspired hydrogels is a promising therapeutic strategy. In addition to anti-cancer effects, hydrogels can also be endowed with other functions, such as the ability to stimulate tissue regeneration, which can effectively improve the healing process after anti-tumor treatment, to obtain better results compared with those of the original treatment.

3.5 Mussel-inspired adhesive hydrogels for other diseases

The spinal cord, an important part of the nervous system, controls sensory and motor functions.^158,159 Traumatic spinal cord injury (SCI) often causes damage to glial cells and neurons, which affects sensory and motor function.^160,161 According to previous reports, modulating the local immune microenvironment, restoring bioelectrical signals, promoting vascularization, and promoting neuronal relay formation are all effective means of promoting spinal cord repair.^162,163 Wang et al. reported a mechano-electro-biomimetic multifunctional adhesion hydrogel (PMEAC) consisting of poly(citrate-maleic)-ε-polylysine (PME), polyethylene glycol diacrylate (PEGDA), and PDA-modified multi-walled carbon nanotubes (MWCNTs) (Fig. 11a-i).¹⁶⁴ As the catechol groups of PDA react with –NH₂ and –SH on the surface of the spinal cord, the PMEAC hydrogel can adhere to the surface of the spinal cord, and it can also effectively adhere to the surface of the skin, polyethylene, and glass (Fig. 11a-ii). Subsequent studies found that the PMEAC hydrogel significantly reduced the number of CD68-positive macrophages and effectively prevented macrophage scattering in the spinal cord (Fig. 11a-iii). These results suggest that the PMEAC hydrogel can effectively promote remyelination and axon regeneration after SCI by regulating the microenvironment of nerve regeneration. The ability of the PMEAC hydrogel to modulate the immune microenvironment comes from polycitrate-based polymers and PDA, which exhibit intrinsic activity and can enhance the M2 antioxidant polarization of macrophages due to their cyclic oligomer structure and orthoquinone structure, respectively.

Chronic inflammatory reactions, mesh exposure, and postoperative hematoma often occur after applying polypropylene mesh (PPM) in pelvic organ prolapse (POP) treatment; therefore, its application is seriously limited.^165–167 To solve this problem, Wu et al. used TA and GelMA to build a hydrogel coating and applied it to the PPM surface (PPM + TA@GelMA) (Fig. 11b-i).¹⁶⁸ Subsequently, PPM + TA@GelMA was implanted in the rat abdominal wall muscle defect model. Owing to the synergistic effect of TA and GelMA, PPM + TA@GelMA had a hemostatic effect, which was beneficial for postoperative hemostasis or to reduce possible hematoma formation. In addition, PPM + TA@GelMA transformed macrophages into M2 macrophages (Fig. 11b-ii), reduced inflammation, promoted collagen fiber regeneration, and promoted angiogenesis, thus aiding in tissue repair.

The brain-machine interface (BMI) establishes communication between external machines and the brain.^169–172 Long-term implantation of BMI may trigger a host immune response, which leads to inaccurate signals and shortens the lifespan of BMI. Through molecular design, we introduced dopamine methacrylate (DMA)-hybridized poly(3,4-ethylenedioxythiophene) nanoparticles (dPEDOT NPs) into the carrageenan-PDA–PAM hydrogel network, a type of mussel-inspired conductive ultrasoft hydrogel (dPEDOT-CA-PDA–PAM) (Fig. 11c-i).⁸⁴ The redox system inside the hydrogel endowed the hydrogel with good bioadhesion and immune escape abilities. The adhesion of the hydrogel ensured that it could be tightly concentrated with metal microcircuits, and it also ensured seamless bonding between the hydrogel BMI and the brain tissue to achieve stable signal transmission (Fig. 11c-ii). In addition, after the hydrogel was implanted subcutaneously in rats, it decreased the expression of TNF-α (M1) and increased the expression of IL-10 (M2) in the surrounding tissue, which reduced nerve inflammation and inhibited the proliferation of fibrous tissue (Fig. 6c).

4. Challenges and prospects

Due to their tunability, high biocompatibility, tissue adhesion, and immunomodulatory properties, mussel-inspired adhesive hydrogels are promising biomaterials in the fields of tissue engineering and anti-tumor therapy, and their immunomodulatory abilities have attracted increasing attention.^{42,76,143,157} In this review, we summarized the development of mussel-inspired adhesive hydrogels, as well as the design strategies and applications of mussel-inspired adhesive hydrogels in tissue engineering and anti-tumor therapy. Recent findings have increasingly shown the great potential of these hydrogels in regulating immune responses for tissue engineering and anti-tumor therapy. In this regard, various strategies have been proposed to control local immunity. Studies have shown that different types of mussel-inspired adhesive hydrogels can modulate local cell immune responses, cooperate with other properties, and effectively promote tissue healing or tumor elimination.

Although there have been many successful results thus far, there are many scientific and technological challenges that remain to be tackled for the development of mussel-inspired hydrogels for local immunomodulation.

(1) Although the current research results of mussel-inspired adhesive hydrogels are promising, there are still some obstacles in translating the research results into clinical application.¹⁷³ One of the main obstacles to the conversion of mussel-inspired adhesive hydrogels into clinical practice is the approval of regulatory authorities.^174,175 The shift from biomaterials for research to industrial manufacturing of therapeutic products requires significant improvements in speed, efficiency, cost and standardization.¹⁷⁶ At present, the design of mussel inspired adhesive hydrogels is diverse, and it may produce an ideal synergistic effect when combined with cells, growth factors or other therapies.²⁷ However, each ingredient adds time and cost, thus affecting the product's market launch.¹⁷⁷ In addition, although the mussel inspired adhesive immunomodulatory hydrogel may be beneficial in the treatment of diseases, its main mechanism is still unclear, leading to unclear regulatory classification.¹⁷⁸ Researchers should consider these regulatory hurdles as early as possible when designing new materials, which is very important for obtaining regulatory approval.

(2) Several studies have confirmed the regulatory effects of mussel-inspired adhesive hydrogels on macrophages.^42,76,79 On the one hand, the hydrogels scavenge ROS through internal catechol groups, thus reducing the M1 polarization of macrophages and inflammatory responses. On the other hand, they promote the M2 polarization of macrophages via the adhesion ability of the catechol groups. However, most studies on mussel-inspired adhesive hydrogels involve only phenotypic changes in macrophages. A variety of immune cells play key roles in the immune response, and there are few studies on the immune response of other cells to hydrogels. Meanwhile, these studies mainly involve the examination of cells and tissues of small animals and lack observations and histological evaluations in humans. Therefore, more experiments or clinical trials are necessary to develop effective mussel-inspired adhesive hydrogels for local immunomodulation.

(3) Little is known about how changes in the physical and chemical properties of mussel-inspired adhesion hydrogels affect immune responses. For example, the hydrophilicity, roughness, stiffness, and surface energy of hydrogels are important factors that affect the immune response.^179–181 Therefore, determining the relationship between these properties and immune cell responses is a new research direction, which will help to construct novel, controllable mussel-inspired adhesive hydrogels for immune modulation.

(4) The immunomodulatory effect of mussel-inspired adhesive hydrogels is not the result of a single factor but the result of the combined effect of various physical and chemical properties. Understanding the properties of mussel-inspired adhesive hydrogels will help improve our understanding of the relevant immune regulatory mechanisms. It is necessary to implement high-throughput screening techniques and artificial intelligence technologies that help to define the parameters of the various components and combinations within the hydrogels; this will enable convenient and rapid screening of specific properties to guide the design of mussel-inspired adhesive hydrogels for local immunomodulation.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by CAMS Innovation Fund for Medical Sciences (CIFMS, 2021-I2M-1-041), the National Natural Science Foundation of China (82072071, 82072073), Guangdong Basic and Applied Basic Research Foundation (2021B1515120019), the Sichuan Science and Technology Program (2022YFS0040), Haihe Laboratory of Cell Ecosystem Innovation Fund (HH22KYZX0040), Shenzhen Funds of the Central Government to Guide Local Scientific and Technological Development (2021SZVUP123), Shanghai Pujiang Program (22PJ1409200), and Fundamental Research Funds for the Central Universities (2682022KJ041, 2682022ZTPY028).

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