Nature-inspired Functional Hydrogel For Biomedical Applications

Functional hydrogels are promising candidates in the field of biomedical materials because they exhibit similar characteristics to human soft tissue,such as high water content,strerchability and flexibility.Functional hydrogel,such as conductive hydrogels,adhesive hydrogels and extracellular matrix(EMC)mimicking hydrogels can be used in a wide range of biomedical applications in the filed of artificial muscles,electronic skin,biosensors and tissue repair.Nowadays,nature materials have been used to prepare functional hydrogels because of their good biocompatibility and degradability.This study developed a variety of hydrogels based on nature materials with multi-functionals,such as conductivity,adhesiveness and tissue regeneration ability.The main content includes the following parts:(1)Conductive hydrogels(CHs)have gained significant attention for their wide applications in biomedical engineering owing to their structural similarity to soft tissue.However,designing CHs that combine biocompatibility with good mechanical and electrical properties is still challenging.Herein,we report a new strategy for the fabrication of tough CHs with excellent conductivity,superior mechanical properties and good biocompatibility by using chitosan framework as molecular templates for controlling conducting polypyrrole(PPy)nanorods in situ formation inside the hydrogel networks.First,polyacrylamide/chitosan(PAM/CS)interpenetrating polymer network(IPN)hydrogel was synthesized by UV photopolymerization;Second,hydrophobic and conductive Py monomers were absorbed and fixed on CS molecular templates,then polymerized with Fe Cl₃ in situ inner hydrophilic hydrogel network.This strategy ensured that the hydrophobic PPy nanorods were uniformly distributed and integrated with the hydrophilic polymer phase to form highly interconnected conductive path in the hydrogel,endowing the hydrogel with high conductivity(0.3 S·m^-1).The CHs exhibited remarkable mechanical properties after the chelation of CS by Fe³⁺and the formation of composites with the PPy nanorods(fracture energy 12000 J·m^-2;compression modulus 136.3 MPa).The use of a biopolymer molecular template to induce the formation of PPy nanostructures is an efficient strategy to achieve conductive multifunctional hydrogels.(2)Conductive polymers are generally insoluble and therefore very difficult to work with,and developing hydrophilic and cell affinitive conductive polymers is significant to broadening the applications of conductive polymer(CP)in biomedical application.In the second part,we designed conductive,redox-active,and hydrophilic lignin-conductive polymer nanoparticles(CP/LS NPs),and then prepared conductive,adhesive,and tough hydrogel based on these NPs.The NPs were prepared by emulsion polymerization,in which sulfonated lignin was complexed with CP chains.These as-prepared CP/LS NPs are redox-active,biocompatible for the existence of LS that contains abundant catechol groups.Moreover,the CP/LS NPs have good water dispersibility and can be incorporated into hydrogels to prepare conductive and adhesive hydrogels.The CP/LS NPs incorporated hydrogels have a good conductivity because the NPs have good water dispersibility and can be uniformly distributed in the hydrogel network to form well-connected electric path.The CP/LS NPs incorporated hydrogel also have long-term adhesive properties,which is attributed to the dynamic redox balance of catechol/quinone groups on the CP/LS NPs.The NPs incorporated hydrogel have good mechanical properties,which is attributed to nano-enhancement effect and noncovalent interaction between the NPs and the chemical-crosslinked polymer network.This conductive and adhesive hydrogel shows good electroactivity and biocompatibility and have wide application in electrostimulation of tissue regeneration and implantable bioelectrodes.(3)Two-dimensional(2D)conductive nanosheets are central to electronic applications because of their large surface areas and excellent electronic properties.However,tuning the multifunctions and hydrophilicity of conductive nanosheets are still challenging.In the third part,we have developed a green strategy for fabricating conductive,redox-active,water-soluble nanosheets via the self-assembly of poly(3,4-ethylenedioxythiophene)(PEDOT)on the polydopamine-reduced and sulfonated graphene oxide(PSGO)template.The conductivity and hydrophilicity of nanosheets are highly improved by PSGO.The nanosheets are redox active due to the abundant catechol groups and can be used as versatile nanofillers in developing conductive and adhesive hydrogels.The nanosheets create a mussel-inspired redox environment inside the hydrogel networks and endow the hydrogel with long-term and repeatable adhesiveness.This hydrogel is biocompatible and can be implanted for bio-signals detection in vivo.This mussel-inspired strategy for assembling 2D nanosheets can be adapted for producing diverse multifunctional nanomaterials,with various potential applications in bioelectronics.(4)Gelatin methacryloyl(Gel MA)hydrogels are widely used for tissue regeneration.Nonetheless,a pure Gel MA hydrogel cannot efficiently serve for cartilage regeneration because of weak mechanical properties and brittleness.In the fourth part,we established a mussel-inspired strategy for tuning the mechanical properties of Gel MA hydrogels by intercalating oligomers of dopamine methacrylate(ODMA)into the chain of Gel MA.After the ODMA intercalated,the hydrogel became tough and resilient.This is because ODMA intercalation reduces the high density of entangled Gel MA chains and introduces additional sacrificial physical cross-linking into the hydrogel.Rheological analysis showed that the ODMA-Gel MA hydrogel was mechanically stable at body temperature.The hydrogel also manifested a sustained protein release because of the ODMA catechol groups.Furthermore,the ODMA-Gel MA hydrogel was found to have good biocompatibility and affinity for cells and tissues because of the catechol groups on ODMA.In vitro,the hydrogel promoted mesenchymal stem cell adhesion and growth,and in vivo,it promoted cartilage regeneration after loading with chondroitin sulfate or TGF-b3.The hydrogel can serve as a growth-factor-free scaffold for cartilage regeneration.This hydrogel not only provided a favorable microenvironment for cartilage repair but also could serve as a promising candidate material for repair of other tissues.This mussel-inspired strategy of introduction of reactive oligomers instead of polymers into a brittle hydrogel network may be extended to the development of other tough hydrogels for biomedical applications.(5)ECM mimicking hydrogel play an important role in cartilage regeneration because they have similar component and mimick the functions of ECM in cartilage.However,most of ECM mimicking hydrogels for cartiliage repair are cell repellant because these hydrogels generally employ negative-charged mucopolysaccharide and therefore they cannot adhere cells and promote tissue regeneration.Herein,we designed a polydopamine(PDA)modified hyaluronic acid(HA)/collagen(Col)cryogel.It was dual crosslinked by repeatly freeze-thaw physical crosslinking and poly(ethylene glycol)diglycidyl ether(PEGDE)chemical crosslinking.This cryogel mimics the ECM of cartilage and can effectively enchance cartilage regeneration.In side the cryogel,HA play an important role in regulating chondrocyte functions,and HA was grafted with polydopamine(PDA)to endow the HA with good cell adhesiveness and tissue adhesiveness.Then,the PDA-g-HA was introduced into the collagen matrix to consruct a cell-affinitive cryogel.Moreover,PDA can fix exogenous growth factor,and capture endogenous growth factor as well.The result of in vitro and in vivo studies demonstrated that the Col/PDA/HA cryogel creates an artificial ECM microenvironment and promotes cartilage repair and regeneration.