Living systems can respond to their environment through signal transduction cascades. In these cascades, original stimuli are amplified and translated into reaction or assembly events. In an effort to instill synthetic materials with biomimetic responsivity, we report an aggregation process forming a supramolecular network held together by host-guest interactions that is responsive to nucleophilic chemical signals through a chemical reaction-assembly cascade. In particular, we developed a signal-induced switch between cucurbit[8]uril binary and ternary complexes with cationic bipyridine derivatives where the charge on the bipyridine can be changed through an allylic substitution reaction with the nucleophilic signal. When applied to a multitopic bipyridine guest, the reaction with the nucleophile signals leads to supramolecular network formation where the aggregation rates and final structure depend on the nucleophilicity of the signal. This work opens the door to new opportunities for signal-responsive synthetic materials and interactions with biological systems.

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Dextran-based hydrogels are promising therapeutic materials for drug delivery, tissue regeneration devices, and cell therapy vectors, due to their high biocompatibility, along with their ability to protect and release active therapeutic agents. This report describes the synthesis, characterization, and application of a new dynamic covalent dextran hydrogel as an injectable depot for peptide vaccines. Dynamic covalent crosslinks based on double Michael addition of thiols to alkynones impart the dextran hydrogel with shear-thinning and self-healing capabilities, enabling hydrogel injection. These injectable, non-toxic hydrogels show adjuvant potential and have predictable sub-millimolar loading and release of the peptide antigen SIINFEKL, which after its release is able to activate T-cells, demonstrating that the hydrogels deliver peptides without modifying their immunogenicity. This work demonstrates the potential of dynamic covalent dextran hydrogels as a sustained-release material for the delivery of peptide vaccines.

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In the quest for stimuli-responsive materials with specific, controllable functions, coacervate hydrogels have become a promising candidate, featuring sensitive responsiveness to environmental signals enabling control over sol-gel transitions. However, conventional coacervation-based materials are regulated by relatively non-specific signals, such as temperature, pH or salt concentration, which limits their possible applications. In this work, we constructed a coacervate hydrogel with a Michael addition-based chemical reaction network (CRN) as a platform, where the state of coacervate materials can be easily tuned by specific chemical signals. We designed a pyridine-based ABA triblock copolymer, whose quaternization can be regulated by an allyl acetate electrophile and an amine nucleophile, leading to gel construction and collapse in the presence of polyanions. Our coacervate gels showed not only highly tunable stiffness and gelation times, but excellent self-healing ability and injectability with different sized needles, and accelerated degradation resulting from chemical signal-induced coacervation disruption. This work is expected to be a first step in the realization of a new class of signal-responsive injectable materials.

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This thesis describes the experimental development of new dynamic hydrogels based on reversible thiol conjugate additions. Redox-controlled hydrogels and self-healing injectable hydrogels have been achieved by introducing reversible thiol conjugate additions to crosslink polymers, leading to hydrogel formation. The overall objective in this thesis was to develop a new fuel-driven transient polymeric hydrogel formation system. Although this final aim was not entirely met, we developed several important concepts along the way, which are described in Chapters 2-5. Chapter 2 describes a new chemical reaction network for fuel-driven transient formation of covalent S-C bonds, based on redox-controlled conjugate addition and elimination. We found that the formation and breaking of covalent bonds in the reaction cycle can be realized in separate reactions, but side reactions hindered the operation in full cycle. If such problems would be solved, this CRN could have potential to be used to form fuel-driven polymer materials. Chapter 3 investigates the formation of a self-healing injectable hydrogel by introducing dynamic thiol-alkynone double addition crosslinks in a polymer network. Such dynamic hydrogels show self-healing and shear thinning properties, confirmed by rheological measurements, macroscopic self-healing, and injection tests. Good cytocompatibility of these hydrogels opens an opportunity for future biomedical applications such as tissue engineering and drug delivery. Chapter 4 describes a redox-controlled reversible thiol-alkynone double addition. First, we created a redox-responsive hydrogel by using such reversible addition for the formation of crosslinks in hydrogels. Second, based on this thiol-alkynone double addition, we developed a fuel-driven transient formation of thiol-alkynone double adduct on small molecules. Chapter 5 explores coupling and decoupling reactions of thiols to an azanorbornadiene bromo sulfone. A self-healing hydrogel can be formed by using azanorbornadiene bromo sulfone to couple two thiol groups together. Such hydrogels are also degradable, trigged by glutathione. Glutathione-triggered dye release experiments suggest this self-healing hydrogel is a potential carrier of drugs, cells or vaccines for biomedical applications. @en

Introduction of dynamic thiol-alkynone double addition cross-links in a polymer network enable the formation of a self-healing injectable polymer hydrogel. A four-arm polyethylene glycol (PEG) tetra-thiol star polymer is cross-linked by a small molecule alkynone via the thiol-alkynone double adduct to generate a hydrogel network under ambient aqueous conditions (buffer pH = 7.4 or 8.2, room temperature). The mechanical properties of these hydrogels can be easily tuned by varying the concentration of polymer precursors. Through the dynamic thiol-alkynone double addition cross-link, these hydrogels are self-healing and shear thinning, as demonstrated by rheological measurements, macroscopic self-healing, and injection tests. These hydrogels can be injected through a 20G syringe needle and recover after extrusion. In addition, good cytocompatibility of these hydrogels is confirmed by cytotoxicity test. This work shows the application of the thiol-alkynone double addition dynamic covalent chemistry in the straightforward preparation of self-healing injectable hydrogels, which may find future biomedical applications such as tissue engineering and drug delivery.@en

Signal transduction in living systems is the conversion of information into a chemical change, and is the principal process by which cells communicate. In nature, these functions are encoded in non-equilibrium (bio)chemical reaction networks (CRNs) controlled by enzymes. However, man-made catalytically controlled networks are rare. We incorporated catalysis into an artificial fuel-driven out-of-equilibrium CRN, where the forward (ester formation) and backward (ester hydrolysis) reactions are controlled by varying the ratio of two organocatalysts: pyridine and imidazole. This catalytic regulation enables full control over ester yield and lifetime. This fuel-driven strategy was expanded to a responsive polymer system, where transient polymer conformation and aggregation are controlled through fuel and catalyst levels. Altogether, we show that organocatalysis can be used to control a man-made fuel-driven system and induce a change in a macromolecular superstructure, as in natural non-equilibrium systems.

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Fuel-driven chemical reaction networks provide an opportunity to develop chemical systems that operate out-ofequilibrium. There remains a need to design and develop new fueldriven chemical reaction networks capable of repeated operation using simple and benign chemistry. Here, we propose a new chemical reaction network for fuel-driven transient formation of covalent bonds,
based on redox-controlled conjugate addition and elimination chemistry. By investigating the separate reactions making up the cycle, we find that the bond formation, breaking and regeneration processes can be realized. At present, substantial side reactivity prevents achieving repeated operation of a full cycle in a single system. If such obstacles would be overcome, this chemical reaction
network could be a valuable addition to the toolbox for out-ofequilibrium
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Hydrazone formation reactions from aldehydes and hydrazides have the remarkable qualities that they proceed in water and the kinetics can be controlled by organocatalysis. For these reasons, this class of reactions finds widespread use in biological as well as material settings. We recently reported a protected aniline catalyst for hydrazone formation that can be activated using a chemical signal. In our search to find a suitable hydrazone formation reaction to investigate the activation of this pro-catalyst, we found a wide variety in reaction rates and response to catalysis. Here we report an overview of hydrazone formation reactions, their reaction rates and response to aniline catalysis, their compatibility for kinetic analysis by UV/Vis spectroscopy, and their compatibility with the reaction environment and with the pro-catalyst pro-aniline.

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