Bio-Multifunctional Hydrogel Patches for Repairing Full-Thickness Abdominal Wall Defects

Developing bio-multifunctional patches with natural extracellular matrix-like structures, excellent high adhesion in the wet state, self-healing ability, antibacterial activity, and favorable cell responses for accelerating tissue healing is highly desirable in clinical applications. Herein, bio-multifunctional composite hydrogels are developed by coupling carboxymethyl chitosan and 4-arm poly (ethylene glycol) aldehyde for full-thickness abdominal wall defect repair. The prepared hydrogels exhibit excellent self-healing and mechanical properties, high adhesion in the wet state, and significant antibacterial ability. In vitro cellular experiments show that the hydrogels combined with recombinant bovine basic fibroblast growth factor remarkably promote cell proliferation and then accelerate full-thickness abdominal wall defect repair in a rat model. The histomorphological evaluation shows that compared to the commercial polypropylene mesh used clinically, the designed hydrogel patches facilitate an increase in the thickness and integrity of the abdominal wall tissue by upregulating the production of Ki67, enhancing the formation of collagen, inducing neovascularization, and inhibiting inflammation by reducing the expression of IL-6, TNF-α, and IL-1β. The results demonstrate that this novel bio-multifunctional hydrogel patch holds great potential for the treatment of full-thickness abdominal wall defects.     

Self‐Healing Silk Fibroin‐Based Hydrogel for Bone Regeneration: Dynamic Metal‐Ligand Self‐Assembly Approach

Despite advances in the development of silk fibroin (SF)‐based hydrogels, current methods for SF gelation show significant limitations such as lack of reversible crosslinking, use of nonphysiological conditions, and difficulties in controlling gelation time. In the present study, a strategy based on dynamic metal‐ligand coordination chemistry is developed to assemble SF‐based hydrogel under physiological conditions between SF microfibers (mSF) and a polysaccharide binder. The presented SF‐based hydrogel exhibits shear‐thinning and autonomous self‐healing properties, thereby enabling the filling of irregularly shaped tissue defects without gel fragmentation. A biomineralization approach is used to generate calcium phosphate‐coated mSF, which is chelated by bisphosphonate ligands of the binder to form reversible crosslinkages. Robust dually crosslinked (DC) hydrogel is obtained through photopolymerization of acrylamide groups of the binder. DC SF‐based hydrogel supports stem cell proliferation in vitro and accelerates bone regeneration in cranial critical size defects without any additional morphogenes delivered. The developed self‐healing and photopolymerizable SF‐based hydrogel possesses significant potential for bone regeneration application with the advantages of injectability and fit‐to‐shape molding.     

Regulation of Stem Cell Fate in a Three‐Dimensional Micropatterned Dual‐Crosslinked Hydrogel System

Micropatterning technology is a powerful tool for controlling the cellular microenvironment and investigating the effects of physical parameters on cell behaviors, such as migration, proliferation, apoptosis, and differentiation. Although there have been significant developments in regulating the spatial and temporal distribution of physical properties in various materials, little is known about the role of the size of micropatterned regions of hydrogels with different crosslinking densities on the response of encapsulated cells. In this study, a novel alginate hydrogel system that can be micropatterned three‐dimensionally is engineered to create regions that are crosslinked by a single mechanism or dual mechanisms. By manipulating micropattern size while keeping the overall ratio of single‐ to dual‐crosslinked hydrogel volume constant, the physical properties of the micropatterned alginate hydrogels are spatially tunable. When human adipose‐derived stem cells (hASCs) are photoencapsulated within micropatterned hydrogels, their proliferation rate is a function of micropattern size. Additionally, micropattern size dictates the extent of osteogenic and chondrogenic differentiation of photoencapsulated hASC. The size of 3D micropatterned physical properties in this new hydrogel system introduces a new design parameter for regulating various cellular behaviors, and this dual‐crosslinked hydrogel system provides a new platform for studying proliferation and differentiation of stem cells in a spatially controlled manner for tissue engineering and regenerative medicine applications.     

Flexible Bicolorimetric Polyacrylamide/Chitosan Hydrogels for Smart Real-Time Monitoring and Promotion of Wound Healing

Real-time monitoring of wound healing remains a major challenge in clinical tissue regeneration, calling the need for the development of biomaterial-guided on-site monitoring wound healing technology. In this study, multifunctional double colorimetry-integrated polyacrylamide-quaternary ammonium chitosan-carbon quantum dots (CQDs)-phenol red hydrogels are presented, aiming to simultaneously detect the wound pH level, reduce bacterial infection, and promote wound healing. The hybridization of CQDs and pH indicator (phenol red) with the hydrogels enables their high responsiveness, reversibility, and accurate indication of pH variability to reflect the dynamic wound status in the context of both ultraviolet and visible light. Furthermore, these visual images can be collected by smartphones and converted into on-site wound pH signals, allowing for a real-time evaluation of the wound dynamic conditions in a remote approach. Notably, the hydrogels exhibit excellent hemostatic and adhesive properties, maintain sufficient wound moisture, and promote wound healing via their high antibacterial activity (against Staphylococcus Aureus, and Escherichia Coli) and skin repair function. Overall, the resulting hydrogels have high potential as a novel smart and flexible wound dressing platform for theranostic skin regeneration.     

Biomimetic Composite Scaffolds to Manipulate Stem Cells for Aiding Rheumatoid Arthritis Management

Stem cell transplantation is a promising alternative therapy for rheumatoid arthritis (RA) patients, with the potential to suppress autoimmune in?ammation and prevent joint damage. However, widespread application of RA therapy based on stem cell transplantation is limited due to poor migration, local retention, and uncontrolled differentiation of stem cells. Here, inspired by the dynamic construction of bone matrix, a structurally and functionally optimized scaffold for loading bone marrow stem cells (BMSCs) is designed to aid RA management. The composite scaffolds consist of stiff 3D printing porous metal scaffolds (3DPMS) and soft multifunctional polysaccharide hydrogels, wherein 3DPMS meet the requirements for large‐scale bone defects caused by RA. Attractively, the fabricated hydrogels on the composite scaffold are self‐healable, injectable, biocompatible, and biodegradable, which endow the resultant scaffold many aspects mimicking the extracellular matrix (ECM). After encapsulation of BMSCs, hydrogels are administered into the inner pores of 3DPMS, abbreviated as BMSCs@3DPMS/hydrogels. In this study, BMSCs@3DPMS/hydrogels have a good effect on improving RA, such as remodeling of knee joint articular cartilage, inhibition of in?ammatory cytokines, and promotion of subchondral bone regeneration. Besides RA, the innovative scaffolds may also serve as an ideal biomaterial for other bone regenerative therapies in various orthopedic diseases.     

双氢青蒿素对骨肉瘤细胞143B影响的研究

目的：研究双氢青蒿素（Dihydroatemisinine,DHA）对人骨肉瘤细胞143B的影响及所导致的形态学变化。方法：采用人骨肉瘤143B细胞株,通过设置对照组和低浓度、中浓度、高浓度的DHA组,H．E染色观察Trandwell小室穿梭能力;划痕愈合实验观察迁移能力;Hoechst33258荧光染色检测细胞凋亡;MTT法检测细胞增殖抑制能力。结果：DHA表现出明显地抑制人骨肉瘤143B细胞的迁移、增殖以及促进凋亡（P〈0．05）,且伴随浓度的递增和时间的延长,抑制作用更明显。结论：DHA具有较强的抗入骨肉瘤作用,其机制可能与DHA诱导骨肉瘤细胞凋亡,并抑制其增殖有关。     

Digital Plasmonic Patterning for Localized Tuning of Hydrogel Stiffness

The mechanical properties of the extracellular matrix (ECM) can dictate cell fate in biological systems. In tissue engineering, varying the stiffness of hydrogels—water‐swollen polymeric networks that act as ECM substrates—has previously been demonstrated to control cell migration, proliferation, and differentiation. Here, “digital plasmonic patterning” (DPP) is developed to mechanically alter a hydrogel encapsulated with gold nanorods using a near‐infrared laser, according to a digital (computer‐generated) pattern. DPP can provide orders of magnitude changes in stiffness, and can be tuned by laser intensity and speed of writing. In vitro cellular experiments using A7R5 smooth muscle cells confirm cell migration and alignment according to these patterns, making DPP a useful technique for mechanically patterning hydrogels for various biomedical applications.     

Highly Efficient Self‐Healable and Dual Responsive Cellulose‐Based Hydrogels for Controlled Release and 3D Cell Culture

To face the increasing demand of self‐healing hydrogels with biocompatibility and high performances, a new class of cellulose‐based self‐healing hydrogels are constructed through dynamic covalent acylhydrazone linkages. The carboxyethyl cellulose‐graft‐dithiodipropionate dihydrazide and dibenzaldehyde‐terminated poly(ethylene glycol) are synthesized, and then the hydrogels are formed from their mixed solutions under 4‐amino‐DL‐phenylalanine (4a‐Phe) catalysis. The chemical structure, as well as microscopic morphologies, gelation times, mechanical and self‐healing performances of the hydrogels are investigated with ¹H NMR, Fourier transform infrared spectroscopy, atomic force microscopy, rheological and compression measurements. Their gelation times can be controlled by varying the total polymer concentration or 4a‐Phe content. The resulted hydrogels exhibit excellent self‐healing ability with a high healing efficiency (≈96%) and good mechanical properties. Moreover, the hydrogels display pH/redox dual responsive sol‐gel transition behaviors, and are applied successfully to the controlled release of doxorubicin. Importantly, benefitting from the excellent biocompatibility and the reversibly cross‐linked networks, the hydrogels can function as suitable 3D culture scaffolds for L929 cells, leading to the encapsulated cells maintaining a high viability and proliferative capacity. Therefore, the cellulose‐based self‐healing hydrogels show potential applications in drug delivery and 3D cell culture for tissue engineering.     

Nonspecific gamma-esterase in the tissues in endometrial cancer

Malignization of endometrium is accompanied by an increase in the production of nonspecific tissue gamma-esterase (NTE). NTE content in uterine tissues and mucus of patients with cancer of endometrium correlates with a degree of differentiation, spreading and depth of tumour cell invasion into the myometrium. The synthesis of NTE occurs in epithelial cells of the endometrium glands which secrete it into the uterus cavity.     

Injectable 3D-Printed Porous Scaffolds for Adipose Stem Cell Delivery and Endometrial Regeneration

Stem-cell-based therapeutic strategies are promising in the clinical treatment of intrauterine adhesions (IUAs), while endometrial regeneration still hardly restores the structure and function of the endometrium because of the inadequate microenvironment for the grafted stem cells and subsequent limited therapeutic efficiency. Herein, an injectable porous hydrogel scaffold (PH scaffold) with customizable shapes is presented by using a microfluidic-based 3D printing technique for adipose-derived stem cells (ADSCs) delivery to enhance endometrial regeneration. These scaffolds display a controllable interconnected porous structure, which not only facilitates the encapsulation of ADSCs within the scaffold but also supports the recovery to their original shapes after injection. Furthermore, the cell viability of the laden ADSCs is well-maintained post-injection, exhibiting promotive effects on cell migration, proliferation, and tube formation. Based on these features, an ADSCs-laden PH scaffold with a hollow endometrium-mimicking morphology is designed and in situ injected into the damaged endometrium in rats of IUAs. These results show that the ADSCs-laden PH scaffolds can enhance functional endometrial regeneration by suppressing the inflammatory response, promoting cell proliferation, and improving vascularization. Thus, it is believed that such unique 3D-printed porous scaffolds are promising candidates for cell delivery, which also provides a minimally-invasive and effective strategy for endometrial regeneration.     

Peptide Hydrogels—A Tissue Engineering Strategy for the Prevention of Oesophageal Strictures

Endoscopic treatment of Barrett's oesophagus often leads to further damage of healthy tissue causing fibrotic tissue formation termed as strictures. This study shows that synthetic, self‐assembling peptide hydrogels (PeptiGelDesign) support the activity and function of primary oesophageal cells, leading to epithelialization and stratification during in vitro 3D co‐culture. Following buffering in culture media, rat oesophageal stromal fibroblasts (rOSFs) are incorporated into a library of peptide hydrogels, whereas mouse oesophageal epithelial cells (mOECs) are seeded on the surface. Optimal hydrogels (PGD‐AlphaProC and PGD‐CGD2) support mOEC viability (>95%), typical cell morphology (cobblestone‐like), and slower migration over a shorter distance compared to a collagen control, at 48 h. Positive expression of typical epithelial markers (ZO‐1 and cytokeratins) is detected using immunocytochemistry at day 3 in culture. Furthermore, optimal hydrogels are identified which support rOSF viability (>95%) with homogeneous distribution when incorporated into the hydrogels and also promote the secretion of collagen type I detected using an enzyme linked immunosorbent assay (ELISA), at day 7. A 3D co‐culture model using optimal hydrogels for both cell types supports a stratified epithelial layer (expressing involucrin and AE1/AE3 markers). Findings from this study could lead to the use of peptide hydrogels as a minimally invasive endoscopic therapy to manage oesophageal strictures.     

Microfluidic 3D Printing Responsive Scaffolds with Biomimetic Enrichment Channels for Bone Regeneration

Tissue-engineered scaffolds have been extensively explored for treating bone defects; however, slow and insufficient vascularization throughout the scaffolds remains a key challenge for further application. Herein, a versatile microfluidic 3D printing strategy to fabricate black phosphorus (BP) incorporated fibrous scaffolds with photothermal responsive channels for improving vascularization and bone regeneration is proposed. The thermal channeled scaffolds display reversible shrinkage and swelling behavior controlled by near-infrared irradiation, which facilitates the penetration of suspended cells into the scaffold channels and promotes the prevascularization. Furthermore, the embedded BP nanosheets exhibit intrinsic properties for in situ biomineralization and improve in vitro cell proliferation and osteogenic differentiation. Following transplantation in vivo, these channels also promote host vessel infiltration deep into the scaffolds and effectively accelerate the healing process of bone defects. Thus, it is believed that these near-infrared responsive channeled scaffolds are promising candidates for tissue/vascular ingrowth in diverse tissue engineering applications.     

Bioinspired Development of an In Vitro Engineered Fracture Callus for the Treatment of Critical Long Bone Defects

Cell-based regenerative constructs provide hope for the restoration of tissue function in compromised biological conditions such as complex bone defects. A strategy mimicking the cascade of events of postnatal fracture healing suggests an implant design where progenitor cells provide the driving force for the construct's tissue forming capacity, while framing biomaterials provide cells with 3D cues to direct cellular processes. Large bone defects mainly heal through the formation of an intermediate endochondral fracture callus. The authors aimed to develop an in vitro engineered fracture callus manufactured by bioprinting to provide a spatially organized tissue construct based on: i) in vitro 3D primed human periosteum derived cells and ii) biocompatible thiol-ene alginate hydrogels, mimicking the cells and extracellular matrix present in the different zones of the callus. Cell viability and maintained osteochondrogenic differentiation upon bioprinting is confirmed in vitro. In vivo assessment displays that the developed biomaterials provided essential 3D cues that further guided the cells in their tissue forming process in the absence of additional stimulatory molecules. The reported findings confirm the appeal of a biomimetic approach to steer tissue development of in vitro engineered constructs and illustrate the suitability of bioprinting methodologies for the fabrication of living regenerative implants.     

Injectable Self‐Healing Antibacterial Bioactive Polypeptide‐Based Hybrid Nanosystems for Efficiently Treating Multidrug Resistant Infection,Skin‐Tumor Therapy,and Enhancing Wound Healing

The surgical procedure in skin‐tumor therapy usually results in cutaneous defects, and multidrug‐resistant bacterial infection could cause chronic wounds. Here, for the first time, an injectable self‐healing antibacterial bioactive polypeptide‐based hybrid nanosystem is developed for treating multidrug resistant infection, skin‐tumor therapy, and wound healing. The multifunctional hydrogel is successfully prepared through incorporating monodispersed polydopamine functionalized bioactive glass nanoparticles (BGN@PDA) into an antibacterial F127‐ε‐Poly‐L‐lysine hydrogel. The nanocomposites hydrogel displays excellent self‐healing and injectable ability, as well as robust antibacterial activity, especially against multidrug‐resistant bacteria in vitro and in vivo. The nanocomposites hydrogel also demonstrates outstanding photothermal performance with (near‐infrared laser irradiation) NIR irradiation, which could effectively kill the tumor cell (>90%) and inhibit tumor growth (inhibition rate up to 94%) in a subcutaneous skin‐tumor model. In addition, the nanocomposites hydrogel effectively accelerates wound healing in vivo. These results suggest that the BGN‐based nanocomposite hydrogel is a promising candidate for skin‐tumor therapy, wound healing, and anti‐infection. This work may offer a facile strategy to prepare multifunctional bioactive hydrogels for simultaneous tumor therapy, tissue regeneration, and anti‐infection.     

Charge-Driven Self-Assembled Microspheres Hydrogel Scaffolds for Combined Drug Delivery and Photothermal Therapy of Diabetic Wounds

The treatment of diabetic wound remains a big clinical challenge. Hydrogel that can provide physical barrier and humidity displays amazing potentials for managing the diabetic wounds healing. Herein, a new charge-driven self-assembled microsphere hydrogel scaffold (SMHS) is reported based on an electric charge interaction, by combining use of black phosphorus (BP)-contained chitosan methacryloyl (CS) microspheres with positive charge and basic fibroblast growth factor-contained hyaluronic acid methacryloyl (HA) microspheres with negative charge. The weak charge attraction among microspheres gives the SMHS the injectable characteristic. Due to the existence of BP, near-infrared (NIR) irradiation has obvious effects on the degradation and drug release behaviors of SMHS. Significantly, SMHS that combines the short-term physical (photothermal) intervention and long-term chemical (drug release) intervention may be promising in spatio-temporal regulation of regenerative microenvironment. SMHS with NIR irradiation (SMHS+NIR) can promote cell proliferation, cell migration, angiogenesis and macrophage polarization. Moreover, in diabetic rat skin wounds, SMHS+NIR significantly accelerates the wound healing process by simultaneously inhibiting the inflammatory response, promoting angiogenesis and tissues remodeling. The outcome of this research not only provides a biomaterial for diabetic wounds healing, but also demonstrates a new strategy for designing novel hydrogel-based biomaterials which have the free editing and combination functions.     

Black‐Phosphorus‐Incorporated Hydrogel as a Conductive and Biodegradable Platform for Enhancement of the Neural Differentiation of Mesenchymal Stem Cells

Conductive hydrogel scaffolds have important applications for electroactive tissue repairs. However, the development of conductive hydrogel scaffolds tends to incorporate nonbiodegradable conductive nanomaterials that will remain in the human body as foreign matters. Herein, a biodegradable conductive hybrid hydrogel is demonstrated based on the integration of black phosphorus (BP) nanosheets into the hydrogel matrix. To address the challenge of applying BP nanosheets in tissue engineering due to its intrinsic instability, a polydopamine (PDA) modification method is developed to improve the stability. Moreover, PDA modification also enhances interfacial bonding between pristine BP nanosheets and the hydrogel matrix. The incorporation of polydopamine‐modified black phosphorous (BP@PDA) nanosheets into the gelatin methacryloyl (GelMA) hydrogels significantly enhances the electrical conductivity of the hydrogels and improves the cell migration of mesenchymal stem cells (MSCs) within the 3D scaffolds. On the basis of the gene expression and protein level assessments, the BP@PDA‐incorporated GelMA scaffold can significantly promote the differentiation of MSCs into neural‐like cells under the synergistic electrical stimulation. This strategy of integrating biodegradable conductive BP nanomaterials within a biocompatible hydrogel provides a new insight into the design of biomaterials for broad applications in tissue engineering of electroactive tissues, such as neural, cardiac, and skeletal muscle tissues.     

Self‐Assembled Injectable Nanocomposite Hydrogels Stabilized by Bisphosphonate‐Magnesium (Mg2+) Coordination Regulates the Differentiation of Encapsulated Stem Cells via Dual Crosslinking

Nanocomposite hydrogels consist of a polymer matrix embedded with nanoparticles (NPs), which provide the hydrogels with unique bioactivities and mechanical properties. Incorporation of NPs via in situ precipitation in the polymer matrix further enhances these desirable hydrogel properties. However, the noncytocompatible pH, osmolality, and lengthy duration typically required for such in situ precipitation strategies preclude cell encapsulation in the resultant hydrogels. Bisphosphonate (BP) exhibits a variety of specific bioactivities and excellent binding affinity to multivalent cations such as magnesium ions (Mg²⁺). Here, the preparation of nanocomposite hydrogels via self‐assembly driven by bisphosphonate‐Mg²⁺ coordination is described. Upon mixing solutions of polymer bearing BPs, BP monomer (Ac‐BP), and Mg²⁺, this effective and dynamic coordination leads to the rapid self‐assembly of Ac‐BP‐Mg NPs which function as multivalent crosslinkers stabilize the resultant hydrogel structure at physiological pH. The obtained nanocomposite hydrogels are self‐healing and exhibit improved mechanical properties compared to hydrogels prepared by blending prefabricated NPs. Importantly, the hydrogels in this study allow the encapsulation of cells and subsequent injection without compromising the viability of seeded cells. Furthermore, the acrylate groups on the surface of Ac‐BP‐Mg NPs enable facile temporal control over the stiffness and crosslinking density of hydrogels via UV‐induced secondary crosslinking, and it is found that the delayed introduction of this secondary crosslinking enhances cell spreading and osteogenesis.     

Engineering Bioactive M2 Macrophage-Polarized Anti-Inflammatory,Antioxidant, and Antibacterial Scaffolds for Rapid Angiogenesis and Diabetic Wound Repair

Diabetic wound healing still faces great challenges due to the excessive inflammation, easy infection, and impaired angiogenesis in wound beds. The immunoregulation of macrophages polarization toward M2 phenotype that facilitates the transition from inflammation to proliferation phase has been proved to be an effective way to improve diabetic wound healing. Herein, an M2 phenotype-enabled anti-inflammatory, antioxidant, and antibacterial conductive hydrogel scaffolds (GDFE) for producing rapid angiogenesis and diabetic wound repair are reported. The GDFE scaffolds are fabricated facilely through the dynamic crosslinking between polypeptide and polydopamine and graphene oxide. The GDFE scaffolds possess thermosensitivity, self-healing behavior, injectability, broad-spectrum antibacterial activity, antioxidant and anti-inflammatory ability, and electronic conductivity. GDFE effectively activates the polarization of macrophages toward M2 phenotype and significantly promotes the proliferation of dermal fibroblasts, the migration, and in vitro angiogenesis of endothelial cells through paracrine mechanisms. The in vivo results from a full-thickness diabetic wound model demonstrate that GDFE can rapidly promote the diabetic wound repair and skin regeneration, through fast anti-inflammation and angiogenesis and M2 macrophage polarization. This study provides highly efficient strategy for treating diabetic wound repair through designing the M2 polarization-enabled anti-inflammatory, antioxidant, and antibacterial bioactive materials.     

Impact of Reactive Amphiphilic Copolymers on Mechanical Properties and Cell Responses of Fibrin‐Based Hydrogels

Mechanical properties of hydrogels can be modified by the variation of structure and concentration of reactive building blocks. One promising biological source for the synthesis of biocompatible hydrogels is fibrinogen. Fibrinogen is a glycoprotein in blood, which can be transformed enzymatically to fibrin playing an important role in wound healing and clot formation. In the present work, it is demonstrated that hybrid hydrogels with their improved mechanical properties, tunable internal structure, and enhanced resistance to degradation can be synthesized by a combination of fibrinogen and reactive amphiphilic copolymers. Water‐soluble amphiphilic copolymers with tunable molecular weight and controlled amounts of reactive epoxy side groups are used as reactive crosslinkers to reinforce fibrin hydrogels. In the present work, copolymers that can influence the mechanical properties of fibrin‐based hydrogels are used. The reactive copolymers increase the storage modulus of the hydrogels from 600 Pa to 30 kPa. The thickness of fibrin fibers is regulated by the copolymer concentration. It could be demonstrated that the fibrin‐based hydrogels are biocompatible and support cell proliferation. Their degradation rate is considerably slower than that of native fibrin gels. In conclusion, fibrin‐based hydrogels with tunable elasticity and fiber thickness useful to direct cell responses like proliferation and differentiation are produced.     

Immunomodulatory Hydrogels: Advanced Regenerative Tools for Diabetic Foot Ulcer

Diabetic foot ulcer (DFU) is one of the most common complications of diabetes, bringing physical and mental challenges for patients due to the lack of efficient curative therapy. Despite considerable advances in pharmacological and surgical approaches, clinical trials for DFU patients remain disappointing due to the local overactive and excessive inflammation. Immunomodulatory hydrogels has significant advantages to overcome the clinical challenge of DFUs therapy. Here, recent fabrication and regenerative advances in the utilization of functional hydrogels for altering the immune microenvironment of DFUs are comprehensively reviewed. The pathological features and the healing processes of DFUs, followed by summarizing the physicochemical properties essential for the design of regenerative hydrogels for immunomodulation in DFUs, are briefly introduced. Then, the potential immuno-therapeutic modalities of hydrogels and emerging trends used to treat DFUs via multitherapeutic approaches and enhanced efficacy and safety are discussed. Taken together, by linking the structural properties of hydrogels to their functions in DFU therapy with a particular focus on immunomodulatory stimuli, this review can promote further advances in designing advanced hydrogels for DFUs, resulting in improved diabetic wound repair through translation into clinical setting in the near future.