Mussel-inspired Hydrogel With Multi-functions For Biomedical Applications

Hydrogels are attractive biomaterials owing to their high water content and structural resemblance to natural soft tissue. Intense efforts have been devoted to synthesizing hydrogels for soft tissue repair,which requires not only toughness,but also cell affinity,tissue adhesiveness, and self-healing ability. However, traditional hydrogels usually exhibit poor mechanical properties due to their high water content; and the commonly reported tough hydrogels lack cell affinity and tissue adhesiveness,and therefore can not fully meet requirements of the practical applications. Recently, mussel-inspired chemistry sheds new light on the development of hydrogels with good cell affinity and tissue adhesiveness. Based on the mussel adhesion mechanism, this study developed a variety tough hydrogels with multi-functions, such as self-adhesiveness, self-healing ability, conductivity, and cell affinity,including the following parts:(1) An ideal hydrogel for biomedical engineering should mimic the intrinsic properties of the natural tissue, especially high toughness and self-healing ability so as to withstand cyclic loading and repair damage as skin and muscle, and excellent cell affinity and tissue adhesiveness to integrate with surrounding tissue after implantation. In this part,a polydopamine-polyacrymide (PDA-PAM) hydrogel was developed, by preventing the over-oxidation of dopamine to maintain enough free catechol groups in the hydrogel.Therefore the hydrogel possesses super stretchability and high toughness, stimuli-free self-healing ability, cell affinity and tissue adhesiveness. More remarkably, the current hydrogel can repeatedly be adhered on/stripped from a variety of substrates for many cycles without loss of adhesion strength. Cell culture experiments proved that the PDA-P AM hydrogels have high affinity to cells. In vivo implantation demonstrated that the PDA-P AM hydrogels accelerate skin tissue regeneration. Furthermore, the hydrogel can serve as an excellent platform to host various nano-building blocks, in which multiple functionalities are integrated to achieve versatile potential applications, such as magnetic and electrical therapies.(2) Adhesive hydrogels are attractive biomaterials for various applications, such as electronic skin, wound dressing, and wearable devices. However, fabricating a hydrogel with both adequate adhesiveness and excellent mechanical properties remains a challenge. In the second part, we used a two-step process to develop an adhesive and tough polydopamine-clay-polyacrylamide (PDA-clay-PAM) hydrogel. Dopamine was intercalated into clay nanosheets and limitedly oxidized between the layers, resulting in PDA-intercalated clay nanosheets containing free catechol groups. Acrylamide monomers were then added and in situ polymerized to form the hydrogel. Unlike previous single-use adhesive hydrogels, our hydrogel showed repeatable and durable adhesiveness. It adhered directly on human skin without causing an inflammatory response and was easily removed without causing damage. The hydrogel also displayed superior toughness,which resulted from nano-reinforcement by clay and PDA-induced cooperative interactions with the hydrogel networks. Moreover, the hydrogel favored cell attachment and proliferation owning to the high cell affinity of PDA. Rat full-thickness skin defect experiments demonstrated that the hydrogel was an excellent dressing. This free-standing, adhesive,tough,and biocompatible hydrogel may be more convenient for surgical applications than adhesives that involve in situ gelation and extra agents.(3) Mucopolysaccharide-based hydrogels are widely used for cartilage repair because they are the main component of extracellular matrix (ECM) in the cartilage and are able to maintain the functions of chondrocytes. However, most of mucopolysaccharide-based hydrogels are negative-charged and cell repellant, and they cannot host cells and favor tissue regeneration. In the third part, we designed a mussel inspired tough and cell affinitive chondroitin sulfate (CS) hydrogel, which can effectively repair cartilage defects without introducing any growth factors or other cytokines. In this hydrogel, polydopamine and CS formed a PDA-CS complex that entangled with polyacrylamide (PAM) chain to form interpenetrated hydrogel, and therefore the hydrogel exhibits resilient, stretchable and tough properties, which meet the mechanical requirement of cartilage repair. Due to the reversible non-covalent interactions introduced by the PDA-CS complex, the CS-PDA-PAM hydrogel exhibit self-healing ability. PDA endows the hydrogel with good cell affinity and tissue adhesiveness. CS plays an important role for regulating chondrocyte functions.Consequently, the CS-PDA-PAM hydrogel creates a growth-factors-free artificial ECM microenvironment for chondrocytes growth and cartilage regeneration. The hydrogel with the combination of toughness, cell affinity, and tissue adhesiveness offered a potential growth-factor-free solution for cartilage repair.(4) Conductive hydrogels are highly desirable and valuable for wearable and implantable biomedical devices for human healthcare; however, conductive hydrogel with multiple functions is still a challenge. Here, we report a conductive hydrogel simultaneously possessing high toughness, self-healability and self-adhesiveness. The hydrogel consists of graphene oxide (GO) and polydopamine (PDA), where GO can be reduced by PDA and the reduction degree of GO is crucial. Partial reduction of GO to graphene endows the hydrogel with good conductivity while remained GO serves as nano-reinforcement for high toughness.Furthermore, the dynamic non-covalent bonds between the unique PDA chains allow the hydrogel to self-heal. Like the adhesion behaviors of mussels, the conductive hydrogel shows self-adhesiveness on various surfaces and integrates well with soft tissue. The hydrogel can be used as an electrical stimulator to regulate cell activity and an implantable electrode for recording in vivo signals. The hydrogel reported herein is a promising candidate for bioelectronics.(6) The major limitation of conductive hydrogels is that they are sensitive to the environment. In the last part, we proposed a novel strategy to develop a mussel-inspired glycerol/water hydrogel (GW-hydrogel), which simultaneously possessed anti-freezing and anti-heating performance, long-term stability, excellent conductivity, super toughness, and self-adhesiveness. The GW-hydrogel was formed in glycerol-water mixture, which endowed the GW-hydrogel with anti-freezing and anti-heating properties. The proposed strategy can be generalized to various functional hydrogels, transforming them into anti-freezing and anti-heating hydrogels. Polydopamine decorated carbon nanotubes were incorporated into the polymer networks to endow the GW-hydrogel with conductivity and adhesiveness,and they also served as nano-reinforcements to enhance the mechanical properties of the GW-hydrogel. The GW-hydrogel can be used as a wearable dressing to protect skin from freezing or burn injury, as demonstrated by the burnt model and the frostbitten models using the back skin of rat. In conclusion, by combination of those properties, the GW-hydrogel is superior to common water-based hydrogels, and a promising material for flexible bioelectronics survival under harsh environments.