Multi-Functional Hydrogel Based On Phenolic Hydroxyl Chemistry And Their Biological Applications

Hydrogels are composed of three-dimensional networks of hydrophilic copolymers or homopolymers,which exhibit the advantages of good flexibility,swelling performance and high water content.However,the properties of traditional hydrogels are relatively simple,and it is difficult to integrate multiple functions into one to build a biomedical application platform with superior performance.In recent years,the reaction mechanism of phenolic hydroxyl chemistry endowed hydrogels with many excellent properties,such as long-term adhesion,anti-inflammatory,anti-oxidative properties and various catalytic activities.In addition,phenolic hydroxyl groups showed high reactivity,thus hydrogels based on phenolic hydroxyl chemistry showed valuable potential in biomedical fields such as regulating cell behavior and promoting tissue repair.Based on the mechanism of phenolic hydroxyl chemical reaction,this study developed multifunctional hydrogels with catalytic activity,antibacterial properties,tissue adhesion and repair properties,including the following parts:（1）Hydrogel bioelectronics are usually required good mechanical properties,electrical conductivity and self-healing properties.However,the preparation of these hydrogels is complicated,requiring chemical crosslinkers,and toxic additives.In addition,the gelation process required external stimuli such as ultraviolet light or heating.It is a huge challenge to preparation of hydrogels with high flexibility,conductivity and self-healing properties at room or low temperatures.In this part,we developed a novel dual self-catalytic system based on a catechol-metal ion complex for efficient and rapid preparation of multifunctional hydrogels.Firstly,the transition metal ions and catechol monomers formed a redox dual-catalytic system,then monomers（acrylic acid or acrylamide）were mixed with it.After adding initiator,it can be quickly polymerized into hydrogel with good mechanical properties(the fracture energy was 1845 J m^-2),electrical conductivity(the electrical conductivity was 38 S m^-1)and self-healing properties.The transition metal ions,which acted as a common oxidant,can oxidize catechol groups.Meanwhile,in the process of oxidation of catechol group,the intermediate product semi-quinone radical generated.The synergistic effect of the two reducing agent constituted a dual self-catalytic system with high catalytic activity.This system can effectively catalyze persulfate to generate of hydroxyl radicals,which initiates the free radical polymerization of the hydrogels.The high efficiency and feasibility of the dual self-catalytic system were verified by a high throughput method.Fe³⁺and DA were used as model materials to explore the catalytic activity and the dual self-catalytic system of hydrogel properties.Fe³⁺can form a variety of non-covalent interactions with catechol groups and hydrogel network,which endowed the hydrogel with good self-healing properties and mechanical properties.The Fe³⁺and catechol monomers were uniformly dispersed in the hydrogel network,which gave the hydrogel a good electrical conductivity.Hydrogels based on this dual self-catalytic system have a wide range of applications in biological electrodes,wearable electronics and other fields.（2）Hydrogels with adhesive properties are widely used in the fields of wound dressings,biological electrodes,tissue repair.Many adhesive hydrogels have limited adhesion ability and cannot achieve long-term adhesion.In addition,adhesive hydrogels often have a single function,making it difficult to integrate multiple functions.These reasons limited the application of adhesive hydrogels as multifunctional biomaterials.Inspired by phenolic hydroxyl chemistry,a mussel-inspired tannic acid chelated-Ag（TA-Ag）nanozyme with peroxidase（POD）-like activity was designed by the in situ reduction of ultrasmall Ag nanoparticles（NPs）with TA.The TA-Ag nanozyme（Φ=5 nm）can catalyze the polymerization of acrylic acid monomers,forming a hydrogel with the properties of long-term adhesion,antibacterial,conductivity properties,and self-setting performance.The long-term adhesion property of the hydrogel was owing to the surface of TA-Ag nanozyme which contained abundant phenolic hydroxyl groups and quinone groups.Moreover,the localized surface plasmon resonance（LSPR）of Ag-NPs can maintain the dynamic balance of phenol/quinone groups.TA-Ag nanozyme was uniformly distributed in the hydrogel network,and formed a variety of non-covalent interactions with the polymer network as the nano-enhancement agent,which improved the mechanical properties of the hydrogel(the fracture energy was 2145 J m^-2).The antibacterial experiment showed that the TA-Ag nanozyme exhibited a good POD-like antibacterial ability,and the wound healing experiment indicated that the TA-Ag hydrogel can promote wound healing and skin tissue regeneration in 21 days.The TA-Ag nanozyme hydrogel showed long-lasting adhesion,antibacterial properties,and promoted tissue regeneration and proliferation.Therefore,this hydrogel can act as an ideal adhesive antibacterial dressing.（3）Collagen（Col）and glycosaminoglycans（GAGs）,as the main components of cartilage extracellular matrix（ECM）,have been widely used in cartilage tissue engineering.Traditional col-based hydrogels lack cartilage tissue-specific cues,and exhibit poor cartilage induction ability,and therefore their application in cartilage repair is limited.Meanwhile,GAGs-based hydrogels exhibit cell-repelling properties due to the negative charge in the polysaccharide molecular chain which hinders cell adhesion and tissue regeneration.Inspired by mussel mechanism,Col and gelatin-methacryloyl（Gel-MA）were used as the main components of the hydrogel network,and p CS-Col/Gel-MA hydrogel with good cell affinity was prepared by integrating polydopamine（PDA）and chondroitin sulfate（CS）.CS modified by PDA（p CS）showed good water solubility and cell affinity,and can be uniformly dispersed in the whole hydrogel network.The p CS-Col/Gel-MA hydrogel showed good cell adhesion property which was attributed to the catechol groups of PDA.CS as a specific active substance of cartilage tissue can effectively promote cartilage regeneration.The results of in vitro and iv vivo studies demonstrated the p CS-Col/Gel-MA hydrogel created a mimicking ECM of cartilage and promoted cartilage regeneration.