The Molecular Mechanism of Polyphenols with Anti-Aging Activity in Aged Human Dermal Fibroblasts

Skin is the largest organ in the body comprised of three different layers including the epidermis, dermis, and hypodermis. The dermis is mainly composed of dermal fibroblasts and extracellular matrix (ECM), such as collagen and elastin, which are strongly related to skin elasticity and firmness. Skin is continuously exposed to different kinds of environmental stimuli. For example, ultraviolet (UV) radiation, air pollutants, or smoking aggravates skin aging. These external stimuli accelerate the aging process by reactive oxygen species (ROS)-mediated signaling pathways and even cause aging-related diseases. Skin aging is characterized by elasticity loss, wrinkle formation, a reduced dermal-epidermal junction, and delayed wound healing. Thus, many studies have shown that natural polyphenol compounds can delay the aging process by regulating age-related signaling pathways in aged dermal fibroblasts. This review first highlights the relationship between aging and its related molecular mechanisms. Then, we discuss the function and underlying mechanism of various polyphenols for improving skin aging. This study may provide essential insights for developing functional cosmetics and future clinical applications.     

Phospholipid Polymer Hydrogel Matrices with Dually Immobilized Cytokines for Accelerating Secretion of the Extracellular Matrix by Encapsulated Cells

Construction of 3D tissues by various types of cells with specific characteristics is an important and fundamental technology in tissue reconstruction medicine and animal‐free diagnosis system. To do so, an excellent extracellular matrix (ECM) is needed for encapsulation of cells and maintaining cell activity. Spontaneously forming hydrogel matrix is used by complexation between two water‐soluble polymers, 2‐methacryloyloxyethyl phosphorylcholine polymer bearing phenylboronic acid groups and poly(vinyl alcohol). Two cytokines for cell proliferation are immobilized in the hydrogel matrix to control the activities of the encapsulated cells. The cytokine‐immobilized hydrogel matrix can encapsulate both L929 fibroblasts and normal human dermal fibroblasts under mild condition. The physical properties of the hydrogel matrix can follow the proliferation process of the encapsulated cells. The encapsulated cells secrete ECM in the polymer hydrogel networks upon 3D culturing for 7 days. Consequently, the tissue‐mimicking ECM hybrid hydrogels are fabricated successfully.     

On‐Demand Dissolution of a Dendritic Hydrogel‐based Dressing for Second‐Degree Burn Wounds through Thiol–Thioester Exchange Reaction

An adhesive yet easily removable burn wound dressing represents a breakthrough in second‐degree burn wound care. Current second‐degree burn wound dressings absorb wound exudate, reduce bacterial infections, and maintain a moist environment for healing, but are surgically or mechanically debrided from the wound, causing additional trauma to the newly formed tissues. We have developed an on‐demand dissolvable dendritic thioester hydrogel burn dressing for second‐degree burn care. The hydrogel is composed of a lysine‐based dendron and a PEG‐based crosslinker, which are synthesized in high yields. The hydrogel burn dressing covers the wound and acts as a barrier to bacterial infection in an in vivo second‐degree burn wound model. A unique feature of the hydrogel is its capability to be dissolved on‐demand, via a thiol–thioester exchange reaction, allowing for a facile burn dressing removal.     

Hydrogel Complex Containing the Antimicrobial Peptide HX-12C Accelerates Healing of Infected Wounds

Bacterial infections of the wound surface can be painful for patients, and traditional dressings do not effectively address this problem. In this study, an antimicrobial wound dressing is prepared using a novel antimicrobial peptide, HX-12C. This hydrogel system is based on the natural biomaterials sodium alginate and gelatin, utilizing calcium carbonate as a source of Ca²⁺, and ionic cross-linking is facilitated by lowering the solution pH. The resulting sodium alginate/gelatin HX-12C-loaded hydrogel (CaAGEAM) has good mechanical and adhesion properties, biocompatibility and in vitro degradability. Its extraordinary antibacterial efficacy (>98%) is verified by an antibacterial experiment. More importantly, in vivo experiments further demonstrate its healing-promotion effect, with a 95% wound healing rate by day 9. Tissue staining demonstrates that the hydrogel containing antimicrobial peptides is effective in suppressing inflammation. The dressing promotes wound healing by stimulating the deposition of skin appendages and collagen. The results of this study suggest that composite hydrogels containing antimicrobial peptides are a promising new type of dressing to promote the healing of infected wounds.     

Hemocompatibility of Ca2+‐Crosslinked Nanocellulose Hydrogels: Toward Efficient Management of Hemostasis

The present work investigates Ca²⁺‐crosslinked nanofibrillated cellulose hydrogels as potential hemostatic wound dressings by studying core interactions between the materials and a central component of wounds and wound healing—the blood. Hydrogels of wood‐derived anionic nanofibrillated cellulose (NFC) and NFC hydrogels that incorporate kaolin or collagen are studied in an in vitro whole blood model and with platelet‐free plasma assays. The evaluation of thrombin and factor XIIa formation, platelet reduction, and the release of activated complement system proteins, shows that the NFC hydrogel efficiently triggered blood coagulation, with a rapid onset of clot formation, while displaying basal complement system activation. By using the NFC hydrogel as a carrier of kaolin, the onset of hemostasis is further boosted, while the NFC hydrogel containing collagen exhibits blood activating properties comparable to the anionic NFC hydrogel. The herein studied NFC hydrogels demonstrate great potential for being part of advanced wound healing dressings that can be tuned to target certain wounds (e.g., strongly hemorrhaging ones) or specific phases of the wound healing process for optimal wound management.     

Preparation of Multi-Functional Quaternary Ammonium Chitosan/Surfactin Hydrogel and its Application in Wound Management

Hydrogel with a 3D network structure can cover the wound to stop the bleeding and support the host tissue infiltration and integration. In this study, an antibacterial hydrogel with hemostasis and the ability to promote wound healing is proposed. This hydrogel comprised surfactin, polyvinylpyrrolidone, and methacrylic anhydride (MA) grafted quaternary ammonium chitosan (CS-MA). The hydrogel formation is triggered by the ultraviolet-initiated polymerization of CS-MA, while the surfactin is complexed with the hydrogel through hydrogen bonding interaction. The results showed that this hydrogel is an adhesive hydrogel with shape adaptability, which can cover the wound surface and promote contact between the hydrogel and the wound surface. More importantly, this hydrogel can simulate the microenvironment of the primary extracellular matrix and increase collagen deposition, and inflammatory factor transformation. The designing of such a multi-functional hydrogel is expected to provide a novel approach to promoting the healing of wounds.     

Bioactive polymeric formulations for wound healing

Ricinoleic acid (RA) has potential to promote wound healing because of its analgesic and anti‐inflammatory properties. This study investigates the synthesis and characterization of RA liposomes infused in a hydrogel for topical application. Lecithin liposomes containing RA were prepared and incorporated into a chitosan solution and were subsequently cross‐linked with di‐aldehyde β‐cyclodextrin (Di‐β‐CD). Chitosan/Di‐β‐CD concentrations and reaction temperatures were varied to alter gelation time, water content, and mechanical properties of the hydrogel in an effort to obtain a wide range of RA release profiles. Hydrogel cross‐linking was confirmed by spectroscopy, and liposome and carrier hydrogel morphology via microscopy. Chitosan, Di‐β‐CD, and liposome concentrations within the formulation affected the extent of matrix swelling, mechanical strength, and pore and overall morphology. Higher cross‐linking density of the hydrogel led to lower water uptake and slower release rate of RA. Optimized formulations resulted in a burst release of RA followed by a steady release pattern accounting for 80% of the encapsulated RA over a period of 48 hours. However, RA concentrations above 0.1 mg/mL were found to be cytotoxic to fibroblast cultures in vitro because of the oily nature of RA. These formulations promoted wound healing when used to treat full thickness skin wounds (2 cm²) in Wister male rats. The wound contraction rates were significantly higher compared to a commercially available topical cream after a time period of 21 days. Histopathological analysis of the RA‐liposomal chitosan hydrogel group showed that the epidermis, dermis, and subcutaneous skin layers displayed an accelerated yet normal healing compared to control group.     

Fabrication and Characterization of an Electro-Compacted Collagen/Elastin/Hyaluronic Acid Sheet as a Potential Skin Scaffold

The development of biomimetic structures with integrated extracellular matrix (ECM) components represents a promising approach to biomaterial fabrication. Here, an artificial ECM, comprising the structural protein collagen I and elastin (ELN), as well as the glycosaminoglycan hyaluronan (HA), is reported. Specifically, collagen and ELN are electrochemically aligned to mimic the compositional characteristics of the dermal matrix. HA is incorporated into the electro-compacted collagen-ELN matrices via adsorption and chemical immobilization, to give a final composition of collagen/ELN/HA of 7:2:1. This produces a final collagen/ELN/hyaluronic acid scaffold (CEH) that recapitulates the compositional feature of the native skin ECM. This study analyzes the effect of CEH composition on the cultivation of human dermal fibroblast cells (HDFs) and immortalized human keratinocytes (HaCaTs). It is shown that the CEH scaffold supports dermal regeneration by promoting HDFs proliferation, ECM deposition, and differentiation into myofibroblasts. The CEH scaffolds are also shown to support epidermis growth by supporting HaCaTs proliferation, differentiation, and stratification. A double-layered epidermal-dermal structure is constructed on the CEH scaffold, further demonstrating its ability in supporting skin cell function and skin regeneration.     

Effects of UVR and UVR-induced cytokines on production of extracellular matrix proteins and proteases by dermal fibroblasts cultured in collagen gels%

Synthesis of extracellular matrix (ECM) proteins and their degradation by matrix metalloproteinases (MMP) are part of the dermal remodeling resulting from chronic exposure of skin to ultraviolet radiation (UVR). We have compared two alternative mechanisms for these responses, namely, a direct mechanism in which UV-B or UV-A is absorbed by fibroblasts and an indirect mechanism in which cytokines, produced in skin in response to UVR, stimulate production of the ECM proteins and MMP. These studies were carried out on human dermal fibroblasts grown in contracted, free-floating 9 day old collagen gels as a dermal equivalent. Synthesis of tropoelastin, collagen, fibrillin, MMP-1, -2, -3 and -9 and tissue inhibitors of metalloproteinases (TIMP)-1 and -2 were measured. Tropoelastin, collagen and fibrillin levels were stable between days 4 and 10, and MMP and TIMP decreased by day 10. Neither UV-B (2.5-50 mJ/cm2) nor UV-A (2-12 J/cm2) altered synthesis of ECM proteins, but UV-A increased MMP-1 and -3 production. Tropoelastin synthesis increased in response to transforming growth factor-beta1 (5 ng/mL) treatment. Both interleukin-1beta and tumor necrosis factor-alpha (10 ng/mL) decreased fibrillin messenger RNA levels but increased MMP-1, -3 and -9 synthesis markedly. Collagen synthesis was not modulated by UV-B, UV-A or cytokine treatment. These results indicate that certain cytokines may have greater effects on production of ECM proteins and MMP than absorption of UV-B and UV-A by fibroblasts grown in dermal equivalents and suggest that the former pathway may play a role in the dermal remodeling in photoaged skin.     

Natural okra-based hydrogel for chronic diabetic wound healing

As a representative of chronic wounds, the long-term high levels of oxidative stress and blood sugar in chronic diabetic wounds lead to serious complications, making them the biggest challenge in the research on wound healing. Many edible natural biomaterials rich in terpenes, phenols, and flavonoids can act as efficient antioxidants. In this study, okra extract was selected as the main component of a wound dressing. The okra extracts obtained via different methods comprehensively maintained the bioactivity of multiple molecules. The robust antioxidant properties of okra significantly reduced intracellular reactive oxygen species production, thereby accelerating the wound healing process. The results showed that okra extracts and their hydrogel dressings increased cell migration, angiogenesis, and re-epithelization of the chronic wound area, considerably promoting wound remodeling in diabetic rats. Therefore, okra-based hydrogels are promising candidates for skin regeneration and wider tissue engineering applications.     

Biologically Active Analogues of the Extracellular Matrix: Artificial Skin and Nerves

Animal development starts as a single cell which proliferates into several new cells; these differentiate into highly specialized tissues, organs, and limbs; and the small but functioning organism eventually grows into its full scale. Throughout development the extracellular matrices, which are complex macromolecular networks, also undergo dramatic changes. Matrix transformations occasionally control the much more well-studied changes in number and type of differentiating cells. Extracellular matrix (ECM) networks are typically broken down enzymatically to oligopeptides and are then resynthesized (remodeled) to form insoluble and nondiffusible macromolecular structures which confer stability of shape to multicellular systems. Mature ECM, such as skin, tendon, cartilage, and blood vessels, provides stiffness and strength to tissues and organs. Remodeling of ECM also occurs in adult organisms, during wound healing. An understanding of the role that ECM plays during development or wound healing can be obtained by use of synthetic ECM analogues. Several simple chemical ECM analogues have been synthesized and a few have been found to possess remarkable biological activity. One of these analogues has induced the partial regeneration of skin in an adult guinea pig wound model as well as in man. Peripheral nerve has been regenerated in another animal model by use of a similar ECM analogue. In all these mammalian lesions it is well-known that regeneration does not occur spontaneously. These analogues are graft copolymers of collagen and chondroitin 6-sulfate (a glycosaminoglycan) in the state of highly hydrated and covalently cross-linked gels. Procedures are summarized for synthesis of copolymers with adjusted physicochemical properties, such as the rate at which they degrade enzymatically when implanted, the elements of their pore structure, and the degree of collagen crystallinity. ECM analogues have provided a novel window into the complexities of morphogenesis and regeneration and they have pointed towards entirely new directions in the medical treatment of serious organ dysfunction and organ loss. An ECM analogue has already become the basis of a new clinical treatment for massively burned patients. An interpretation of the results leads to a hypothesis about the nature of ECM during development. Since biological activity appears only when the physicochemical parameters fall within very narrow limits, it is intriguing to speculate that these experiments describe a single insoluble growth factor which is specific for skin synthesis. Such an insoluble growth factor appears to be just as essential to skin development as are the much more well-known soluble growth factors. A different ECM analogue appears to induce nerve regeneration, possibly because each tissue requires its own developmentally active ECM.     

Silymarin, a flavonoid from milk thistle (Silybum marianum L.), inhibits UV-induced oxidative stress through targeting infiltrating CD11b+ cells in mouse skin

Phytochemicals have shown promise in inhibiting UV-induced oxidative stress, and therefore are considered as potent inhibitors of UV-induced oxidative stress-mediated skin diseases. We have shown previously that topical treatment of silymarin, a flavonoid from milk thistle (Silybum marianum), inhibits UV-induced oxidative stress in mouse skin. However, the cellular targets responsible for the inhibition of UV-induced oxidative stress by silymarin are not clearly defined. To address this issue, C3H/HeN mice were UV irradiated (90 mJ cm(-2)) with or without topical treatment with silymarin (1 mg cm(-2) skin area). Mice were killed 48 h later and skin samples collected. Flow cytometric analysis of viable dermal cells revealed that the number of infiltrating CD11b+ cells were the major source of oxidative stress (31.8%) in UV-irradiated skin compared with non-UV-exposed skin (0.4%). Treatment of silymarin inhibited UV-induced oxidative stress through inhibition of infiltrating CD11b+ cells. The analysis of myeloperoxidase also indicated that silymarin significantly (P < 0.001) decreased UV-induced infiltration of leukocytes, and this effect of silymarin was similar to that of intraperitoneal treatment of mice with monoclonal antibodies to CD11b. The inhibitory effect of silymarin, regardless of whether it is topically treated before or after UV irradiation, was of similar magnitude. Intraperitoneal administration of monoclonal antibodies to CD11b (rat IgG2b) to C3H/HeN mice inhibited UVB-induced oxidative stress generated by both epidermal and dermal cells as is evident by relative fluorescence intensity of oxidized rhodamine. Similar to the effect of anti-CD11b, silymarin also inhibited UV-induced oxidative stress in both epidermal and dermal cells. Further, CD11b+ and CD11b- cell subsets from UV-treated or silymarin+UV-treated mice were separated by immunomagnetic cell isolation technique from total epidermal and dermal single cell suspensions and analyzed for reactive oxygen species (ROS)/H2O2 production. Analytic data revealed that CD11b+ cell population from UV-irradiated skin resulted in significantly higher production of ROS in both epidermis and dermis than CD11b- cell population, and that silymarin inhibited UV-induced oxidative stress through targeting infiltrating the CD11b+ cell type in the skin.     

Hyaluronic acid-methacrylic anhydride/polyhexamethylene biguanide hybrid hydrogel with antibacterial and proangiogenic functions for diabetic wound repair

Diabetic wounds lead to a decrease in quality of life and an increase in mortality. Current treatment strategies include preventing bacterial adhesion while improving microcirculation. As a new type of wound dressing that imitates natural skin, hydrogel has gradually emerged with its excellent properties. However, existing hydrogels rarely achieve satisfactory results in promoting wound repair and antibacterial simultaneously. In this case, we prepared methacrylic anhydride chemically modified hyaluronic acid as a hydrogel matrix, added polyhexamethylene biguanide as an antibacterial component, and loaded sodium alginate/salidroside composite microspheres which could sustainably release salidroside and thus promote angiogenesis. Hybrid hydrogel (HAMA/PHMB-Ms) was synthesized via photocrosslinking, and its chemical structure, particle size distribution and microstructure were characterized. The satisfactory antibacterial properties of the HAMA/PHMB(15%)-Ms hydrogel were studied in vitro, and its antibacterial rates against E. coli and S. aureus were 97.85% and 98.56%, respectively. In addition, after demonstrating its good biocompatibility, we verified that the HAMA/PHMB-Ms hydrogel has increased granulation tissue formation, more collagen deposition, more subcutaneous capillary formation, and better wound healing than blank control, HAMA and HAMA/PHMB hydrogel on the back wound model of diabetic mice. The results confirmed that HAMA/PHMB-Ms hydrogel was a promising material for the treatment of the diabetic wounds.     

Development of Gelatin‐Alginate Hydrogels for Burn Wound Treatment

Hydrogels are interesting as wound dressing for burn wounds to maintain a moist environment. Especially gelatin and alginate based wound dressings show strong potential. Both polymers are modified by introducing photocrosslinkable functionalities and combined to hydrogel films (gel‐MA/alg‐MA). In one protocol gel‐MA films are incubated in alg‐MA solutions and crosslinked afterward into double networks. Another protocol involves blending both and subsequent photocrosslinking. The introduction of alginate into the gelatin matrix results in phase separation with polysaccharide microdomains in a protein matrix. Addition of alg(‐MA) to gel‐MA leads to an increased swelling compared to 100% gelatin and similar to the commercial Aquacel Ag dressing. In vitro tests show better cell adhesion for films which have a lower alginate content and also have superior mechanical properties. The hydrogel dressings exhibit good biocompatibility with adaptable cell attachment properties. An adequate gelatin‐alginate ratio should allow application of the materials as wound dressings for several days without tissue ingrowth.     

Self‐Assembly‐Peptide Hydrogels as Tissue‐Engineering Scaffolds for Three‐Dimensional Culture of Chondrocytes in vitro

The promising potential of a RAD‐16 self‐assembly‐peptide hydrogel as a scaffold for tissue‐engineered cartilage was investigated. Within 3 weeks of in vitro culture, chondrocytes within the hydrogel produced a high amount of GAG and type‐II collagen, which are the components of cartilage‐specific extracellular matrix (ECM). With the culture time increased, toluidine‐blue staining for GAG and immuno‐histochemistry staining for type‐II collagen of the chondrocytes‐hydrogel composites became more intense. Analysis of the gene expression of the ECM molecules also confirmed the chondrocytes in the peptide hydrogel maintained their phenotype within 3 weeks of in vitro culture.

     

Janus hydrogel with dual antibacterial and angiogenesis functions for enhanced diabetic wound healing

Anti-infection and neovascularization at the wound site are two vital factors that accelerate diabetic wound healing. However, for a wound healing dressing, the two functions need to work at different sites(inner and outer), giving big challenges for dressing design. In this study, we fabricated a novel sodium alginate/chitosan(SA/CS) Janus hydrogel dressing by the assembly of SA hydrogel loaded with silver nanoparticles(Ag NPs) and CS hydrogel impregnated with L-arginine loaded sodium alginate ...     

Improvement of dermal burn healing by combining sodium alginate/chitosan-based films and low level laser therapy

This paper aimed to evaluate the improvement of burn wounds healing by sodium alginate/chitosan-based films and laser therapy. Natural polymers with different biological activities are widely used as film dressings to improve wound healing. Lasers arrays accelerate the healing repair of soft tissue injuries. Burn procedures were performed on the backs of 60 male rats assigned into six groups: untreated (CTR), dressed with cellulose films (CL), dressed with sodium alginate/chitosan-based films (SC), laser-irradiated undressed wounds (LT), laser-irradiated wounds with cellulose (CLLT) and sodium alginate/chitosan-based films (SCLT). Laser therapy was applied for 7 days. Animals of each group were euthanised 8 and 14 days after the burn procedures. The inflammatory reaction was significantly more intense in the CTR group than in the irradiated groups after 8 and 14 days. Laser therapy stimulated myofibroblastic differentiation in 8 days, with or without dressing films. Combined laser therapy and both dressings improved epithelisation, blood vessels formation and collagenization, promoted rapid replacement of type III for type I collagen and favored the better arrangement of the newly formed collagen fibres. The combination of laser therapy and sodium alginate/chitosan-based dressing improves burn healing, apparently by modulating the epithelisation, blood vessels formation and collagenization processes.     

The Effect of Rainbow Trout (Oncorhynchus mykiss) Collagen Incorporated with Exo-Polysaccharides Derived from Rhodotorula mucilaginosa sp. on Burn Healing

Burn is one of the physically debilitating injuries that can be potentially fatal; therefore, providing appropriate coverage in order to reduce possible mortality risk and accelerate wound healing is mandatory. In this study, collagen/exo-polysaccharide (Col/EPS 1–3%) scaffolds are synthesized from rainbow trout (Oncorhynchus mykiss) skins incorporated with Rhodotorula mucilaginosa sp. GUMS16, respectively, for promoting Grade 3 burn wound healing. Physicochemical characterizations and, consequently, biological properties of the Col/EPS scaffolds are tested. The results show that the presence of EPS does not affect the minimum porosity dimensions, while raising the EPS amount significantly reduces the maximum porosity dimensions. Thermogravimetric analysis (TGA), FTIR, and tensile property results confirm the successful incorporation of the EPS into Col scaffolds. Furthermore,the biological results show that the increasing EPS does not affect Col biodegradability and cell viability, and the use of Col/EPS 1% on rat models displays a faster healing rate. Finally, histopathological examination reveals that the Col/EPS 1% treatment accelerates wound healing, through greater re-epithelialization and dermal remodeling, more abundant fibroblast cells and Col accumulation. These findings suggest that Col/EPS 1% promotes dermal wound healing via antioxidant and anti-inflammatory activities, which can be a potential medical process in the treatment of burn wounds.     

Acetate chitosan with CaCO3 doping form tough hydrogel for hemostasis and wound healing

In recent years, chitosan has been applied for wound management due to its properties of biocompatibility, biodegradability, antimicrobial activity, and low immunogenicity. But the poor water solubility in neutral pH limited its further application in clinical wound healing. To overcome this problem, acetate chitosan was developed and approved as commercial products for wound healing. However, the acidity of acetate chitosan was potentially allergenic, and the poor mechanical properties of its formed hydrogels also hindered the therapeutic efficacy in wound care. In this study, CaCO₃ was simply doped into acetate chitosan to form the wound dressing. After absorbing water, the H⁺ of acetate chitosan reacted with CaCO₃ to release Ca²⁺, resulting in acidity decreased. The production of Ca²⁺ and residue of CaCO₃ cross‐linked with chitosan to form a tough hydrogel by electrostatic interaction. The physical characteristics, swelling, mechanical testing, and blood clotting were evaluated. The results in vitro demonstrated that after doping CaCO₃ into acetate chitosan, the mechanical properties and blood clotting of the formed hydrogel were increased. Then, the evaluation of hydrogels in vivo revealed that it can also accelerate the wound healing by promoting re‐epithelization and collagen deposition. This simple way by doping CaCO₃ into acetate chitosan can increase wound healing, and it can also broad the application of acetate chitosan in clinical use.     

Bioactive Phenylboronic Acid-Functionalized Hyaluronic Acid Hydrogels Induce Chondro-Aggregates and Promote Chondrocyte Phenotype

Hydrogels are extensively investigated as biomimetic extracellular matrix (ECM) scaffolds in tissue engineering. The physiological properties of ECM affect cellular behaviors, which is an inspiration for cell-based therapies. Photocurable hyaluronic acid (HA) hydrogel (AHAMA-PBA) modified with 3-aminophenylboronic acid, sodium periodate, and methacrylic anhydride simultaneously is constructed in this study. Chondrocytes are then cultured on the surface of the hydrogels to evaluate the effect of the physicochemical properties of the hydrogels on modulating cellular behaviors. Cell viability assays demonstrate that the hydrogel is non-toxic to chondrocytes. The existence of phenylboronic acid (PBA) moieties enhances the interaction of chondrocytes and hydrogel, promoting cell adhesion and aggregation through filopodia. RT-PCR indicates that the gene expression levels of type II collagen, Aggrecan, and Sox9 are significantly up-regulated in chondrocytes cultured on hydrogels. Moreover, the mechanical properties of the hydrogels have a significant effect on the cell phenotype, with soft gels (≈2 kPa) promoting chondrocytes to exhibit a hyaline phenotype. Overall, PBA-functionalized HA hydrogel with low stiffness exhibits the best effect on promoting the chondrocyte phenotype, which is a promising biomaterial for cartilage regeneration.