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ÖgeMechanically strong hyaluronic acid-based hydrogels(Lisansüstü Eğitim Enstitüsü, 2021) Tavşanlı, Burak ; Okay, Oğuz ; 666501 ; KimyaHyaluronan, or hyaluronic acid (HA), is a naturally occurring carbohydrate polymer consists of disaccharide repeating units of β-1,4-D-glucuronic acid - β-1,3-N-acetyl- D-glucosamine. HA is the main component of the extracellular matrix (ECM), and it plays an essential role in the wound-healing processes. HA has become an important building block for creating new biomaterials with utility in tissue engineering and regenerative medicine. Although HA is an attractive biomaterial for soft tissue regeneration due to its distinctive biological functions and lubricating properties, it has limited application areas because of its rapid degradation and poor biomechanical properties. To overcome this drawback, native HA was physically or chemically cross- linked, or alternatively, methacrylate groups were incorporated into HA to generate HA macromers, which are then polymerized to form hydrogels. The resulting hydrogels exhibit poor mechanical properties for use in stress-bearing applications, although the cross-linking of HA decreases its degradation rate and solubility in aqueous media. The lack of mechanical strength in HA hydrogels is primarily due to the lack of viscoelastic dissipation in the chemically cross-linked HA network, resulting in low-stress fracture of the hydrogels. Several techniques including double- network gels (DN), incorporation of additional macromolecules such as silk fibroin (SF), and cryogelation have been developed to enhance the mechanical properties of HA hydrogels. Double-network (DN) technique allows for the development of high-strength hydrogels via two-step sequential free radical polymerization. DN hydrogels are prepared by swelling a brittle and highly cross-linked first network hydrogel in a second monomer solution. After reaching equilibrium, the second monomer is polymerized to form a ductile and loosely cross-linked second network. In general, the mass ratio of second-network to the first-network is very high, and two networks are strongly entangled with each other. Poly(N,N-dimethylacrylamide) (PDMA) is a biocompatible polymer with associative properties and widely used to produce hydrogels. PDMA hydrogels can easily be prepared by free-radical copolymerization of N,N-dimethylacrylamide (DMA) in bulk or in aqueous solution in the presence of a cross-linker. Recently, a novel triple-network (TN) approach has been developed for preparing mechanically robust nonionic polyacrylamide (PAAm)/PDMA/PDMA hydrogels in our research group. A great variety of hydrogels exhibiting different mechanical properties have been fabricated by tuning the mass ratio of the consecutive networks. The TN approach relies on a second monomer translational entropy loss upon polymerization with the first network. Silk fibroin (SF) derived from Bombyx mori cocoons is a biopolymer that offers several features comprising biocompatibility, controlled biodegradability, and unique mechanical properties. The primary structure of SF includes repetitive blocks of high molecular weight hydrophobic and low molecular weight hydrophilic chains. Structural arrangements in the hydrophobic blocks form β-sheet structure, which is responsible for its high strength, whereas hydrophilic blocks provide water solubility and toughness. Hydrogels derived from SF are attractive soft materials in biomedical applications; however, they exhibit poor mechanical properties limiting their load- bearing applications. In order to fabricate macroporous hydrogels of high toughness and fast responsiveness, there is a facile and versatile technique called cryogelation. During this process, the solvent, mainly water, is used as a porogen in order to form a highly interconnected porous structure. Thus, the cross-linking reactions take place below the freezing point of the reaction medium. As water freezes, frozen solvent crystals and unfrozen liquid system containing concentrated monomer or polymer solution form. After cryogelation, a polymer network with a porous structure is obtained. The aim of this thesis is to produce HA hydrogels exhibiting extraordinary mechanical performances. Firstly, sequential polymerization reactions were conducted to produce HA/PDMA double- and HA/PDMA/PDMA triple-network hydrogels starting from native and methacrylated HA (GMHA). Next, one-pot synthesis of HA hydrogels was introduced to shorten the reaction time and to reduce the amount of reagents used. For this purpose, DMA or methacrylic acid (MAAc), and DMA and SF were incorporated separately into a reaction solution containing GMHA and then polymerized to produce HA hydrogels. Lastly, to produce robust macroporous HA hydrogels, the cryogelation technique was conducted at sub-zero temperatures starting from GMHA in the presence of DMA monomer. The thesis presented here resulted in five publications, mainly based on fabricating mechanically strong HA hydrogels. Within each following section, the mechanical properties of HA hydrogels and cryogels were investigated in detail and their internal structures were clarified by various techniques. In the first part of the thesis, HA hydrogels were prepared by utilizing a two-step process. Primarily, HA was chemically cross-linked in aqueous solutions using ethylene glycol diglycidyl ether (EDGE) under different experimental conditions. EGDE cross-linked HA hydrogels containing 97-99% water were fragile and ruptured when compressed to 25-51% strain under 0.02-0.15 MPa stresses. By applying the double-network (DN) approach in the second step, high strength DN hydrogels containing 84-94% water were generated. Shortly, single-network brittle HA hydrogels were first swollen in aqueous N,N-dimethylacrylamide (DMA) solutions containing a small amount of BAAm cross-linker, and then photopolymerized to form a loosely cross-linked poly(N,N-dimethylacrylamide) (PDMA) second network. Adjusting the first and second network components ratio resulted in hydrogels exhibiting a compressive modulus of 0.9 MPa that sustain 19.4 MPa compressive stresses. Cyclic mechanical tests show irreversible stress-strain curves with a large hysteresis, indicating that the elastically effective cross-links of HA first-network are irreversibly destroyed under load by dissipating energy. In the second part of the thesis, triple-network (TN) hydrogels based on GMHA and DMA were prepared by sequential free radical photopolymerizations. Multifunctional GMHA macromers, used as the first network component, were prepared with various metacrylation degrees and characterized by H-NMR technique. DN hydrogels were prepared by swelling SN hydrogels in DMA solutions containing a small amount of BAAm cross-linker, following by photopolymerization. This leads to the formation of GMHA/PDMA hydrogels with a compressive modulus and fracture stress of up to 0.4 MPa and 12 MPa, respectively. Due to the reduction of the second monomer's translational entropy after photopolymerization, an additional monomer solution could be introduced to DN hydrogels to obtain GMHA/PDMA/PDMA TN hydrogels that sustain compressive stresses above 20 MPa. Cyclic mechanical tests showed that, although TN hydrogels internally fracture even under small strain, the ductile components hinder macroscopic crack propagation by keeping the macroscopic gel samples together. In the third part of this study, a simple one-pot synthesis of HA hydrogels via free- radical copolymerization of GMHA and DMA in aqueous solutions were introduced. It was found that GMHA acts as a multifunctional cross-linker during its copolymerization with DMA leading to the formation of interpenetrated and interconnected polymer networks. The effective functionality of GMHA increases with its degree of methacrylation as well as with the DMA concentration. The viscoelastic and mechanical properties of HA hydrogels could be tuned by varying the degree of methacrylation of GMHA and DMA concentration. A significant improvement in the mechanical performance of the hydrogels was observed when DMA is replaced with methacrylic acid monomer. By adjusting the synthesis parameters, hydrogels with a Young's modulus of around 200 kPa could be prepared that sustain up to 20 MPa stresses at 96% compression. In the fourth part, mechanically robust and stretchable SF/HA hydrogels were prepared from GMHA and SF in aqueous solutions in the presence of a radical initiator. DMA monomer was also included in the reaction solution as a spacer to connect GMHA's through their pendant vinyl groups. After incorporating SF into the gel network, Young's modulus and fracture stress of the as-prepared hydrogels increased markedly from 5 to 54 kPa and from 0.6 to 4.9 MPa, respectively. Additionally, and most importantly they sustain up to 400% stretch ratio under a stress of 80 kPa. The presence of SF significantly enhances the mechanical strength of HA hydrogels due to its β- sheet domains, which was confirmed by XRD measurements, acting as physical cross- links. The damage in the SF network under large strain leads to a significant energy dissipation, which is responsible for the improved mechanical properties of SF/HA hydrogels. In the last part of this study, the preparation of HA cryogels via free-radical copolymerization of methacrylated HA and DMA in aqueous solutions was presented. By adjusting both the methacrylation degree of HA and DMA concentration, we were able to produce cryogels exhibiting Young's modulus up to around 350 kPa and compressive fracture stress of above 3 MPa. HA cryogels have an interconnected pore structure with pores of >90 μm in diameter and exhibit a high porosity (>97%), as observed by scanning electron microscopy (SEM) and micro-computed tomography analysis (μ-CT). HA cryogels are squeezable, and no crack propagation occurred when compressed up to 99% strain. They also exhibit a very fast swelling-deswelling behavior in good and poor solvents, respectively. Increasing the degree of methacrylation of HA or DMA concentration reduces the swelling ratio, porosity and pore size of the cryogels. Moreover, the fracture stress of dried cryogels increases with increasing DMA concentration, whereas in their swollen states, an opposite behavior was observed. This unusual behavior could be explained with the water content of the cryogels under large strain conditions.