Functionalized hydrogel for oral hard tissue regeneration
Oral hard tissue refers to the hard and mineralized tissues, such as enamel, dentin, and bone, which form an integral complex, playing a vital role in aesthetics and oral functions. The osteochondral complex of temporomandibular joint (TMJ) also functions to dissipate or transfer the masticatory force. In this thesis, we mainly focused on the regeneration of dentin, bone and osteochondral complex by using functionalized hydrogels. In chapter 2, we developed injectable colloidal gels through a simple UV method from methacrylic acid functionalized gelatin (Gel-MA) loaded with notoginsenoside R1 (Gel-MA/NGR1) for reparative dentin regeneration. Our results showed that the hydrogel retained porous inner structure and hydrophilicity with a sustained drug release. Gel-MA/NGR1 hydrogel could significantly promote in-vitro dentinogenic markers, extracellular matrix mineralization, and in-vivo reparative dentin formation in comparison with Gel-MA. These findings suggested a promising application potential of Gel-MA/NGR1 in pulp-capping techniques. The avascular structure and lack of regenerative cells make the repair of osteochondral defects in the TMJ highly challenging in clinic. To provide a viable treatment option, in chapter 3, we developed a histatin-1 (Hst1)-functionalized Gel-MA hydrogel to combine the chondroconductive property of Gel-MA and the cell-activating capacity of Hst1 to repair the critical-size osteochondral defects in TMJ. Our data showed that Hst1/Gel-MA hydrogel group possessed a significant higher International Cartilage Repair Society (ICRS) score and Modified Oâ€˜Driscoll Score (MODS) in comparison with the Gel-MA group and control group. Furthermore, histomorphometric analysis showed significantly higher expression of collagen II, aggrecan, collagen fiber, GAG, and more newly formed subchondral bone and cartilage in Hst1/Gel-MA hydrogel group than the Gel-MA group and control group. The usage of Gel-MA may not be very suitable for the partially exposed defects, such as, jumping gap in immediate implantation since the long and narrow geometry of, and the bleeding in jumping gap may largely hinder the photocrosslinking-based gelation process and lead to insufficient gelation. To approach this situation, we resorted to another type of hydrogel â€” injectable self-healing hydrogels with dynamic crosslinking, which could be gelled without the needs of additional chemical/physical initiations. In chapter 4, we adopted gelatin and oxidized alginate (OSA) to construct an injectable self-healing hydrogel. The physicochemical and in-vitro and in-vivo biological characterization showed that the self-healing hydrogels could support cell survival, proliferation, and migration, and had a good injectability, in-situ gelation, and biocompatibility, suggesting a promising candidate for tissue engineering scaffold and drug delivery vehicle. In comparison with conventional osteconductive CaP-based bone filling materials, an injectable, self-healing and pro-osteogenic hydrogel will be more suitable to fill large jumping gap and preserve buccal bone. In chapter 5, we developed an injectable self-healing sericin/oxidized alginate hydrogel (SS/OSA), and functionalized the hydrogel with a pro-osteogenic agent â€•salvianolic acid B (SAB). The results suggested that the SS/OSA-SAB hydrogel might be a promising scaffold candidate for promoting bone regeneration in jumping gaps. Barrier membrane is an indispensable element in GBR technique to prevent the invasion of surrounding connective tissues that bears proliferation advantage over osteoblasts so as to facilitate bone tissue regeneration. Gel-MA bears certain stickiness to mineralized tissue and UV crosslinking is also very suitable for this application. However, the mechanical property of Gel-MA should still be improved to be used as a GBR membrane. In chapter 6, we adopted a hybrid-crosslinking method (Schiffâ€™s base reaction and UV initiated polymerization) to develop an in-situ formed barrier membrane with enhanced mechanical property and osteogenesis. In this thesis, we adopted different bioactive agents or ECM components to functionalize hydrogels with enhanced mechanical and pro-osteogenic/dentinogenic properties. These data suggested a promising potential of the functionalized hydrogels in the regeneration of oral hard tissues.