Signal transduction in living systems enables adaptive and interactive response to external stimuli. These rudimentary primary processes developed by nature are currently absent in synthetic materials. Implementing these processes in materials can have widespread advances in regenerative medicine, diagnostics or nanomachines. Taking inspiration from nature, organocatalytic reactions will be used in the design of new strategies for signal-responsive materials. These systems undergo physical or mechanical changes in response to stimuli triggered chemical transformations, enabling signal-recognition, signal- translation and ultimately leading to pre-programmed material response. In this thesis, small molecules, usually used as organocatalysts, are implemented in materials to develop signal-triggered and autonomous systems for applications such as controlled drug delivery, autonomous actuators or detection platforms...

Smart materials are materials that are capable of responding in a programmable and predictive manner. Such materials respond to a broad variety of internal and external triggers and modulate one or more material properties accordingly. Common material responses are controlled release, color changes, morphological changes or changing the mechanical properties of the bulk material. Well known examples of smart materials in our life are chromoactive materials in sunglasses or windows that change color or transparency when subjected to (sun)light, self-healing concrete and plastics or shape memory materials being responsive to heat. Smart materials often reside in a stationary phase, where built-in molecular functionality can respond autonomously to a changing environment. A material’s response can be triggered by many different stimuli having a chemical nature (e.g. pH, salts and metals), biochemical nature (e.g. peptides, nucleic acids, metabolites and polysaccharides) or a physical nature (e.g. temperature, light, magnetic field and pressure). Materials constructed from polymers, particles or gels can be used for applications such as self-healing, sensing, tissue engineering and drug delivery. Smart materials described in this thesis are designed to respond to signaling molecules, UV light, gamma-radiation or mechanical force. In the following subsections these triggers will be discussed in detail.

Treatment of cancer requires local medication at the tumor site to prevent side-effects of chemotherapy. Nanocarriers, such as micelles, can be used to transport drugs to the tumor site and limit side effects of cancer treatment. Micelles are easy to produce, have a high solubilization potential for hydrophobic drugs and therefore can have high loading capacity. Due to the increase in cell division and higher activity of cancer cells, elevated levels of reactive oxygen species (ROS) are often present at the tumor site. ROS have a highly oxidizing agent property by damaging DNA of cancer cells, it can be used to treat tumors. Beside ROS formation of the metabolic cycle, ROS can also be produced by ionizing radiation. With radiolysis of water, caused by radiation, the ROS concentrations at tumor sites can be increased. This research aimed to prepare micelles made from a block copolymer, that are sensitive to ROS and that are sensitive to ROS formed by radiolysis of water with gamma radiation for drug release purposes. 4-(methylthio)phenyl acrylate (MTPA) groups present in the block copolymer (PDMA-MTPA), are sensitive for oxidation reactions which will lead to decomposition of the polymer, and thus of the micelles. During this research, micelles with a hydrodynamic diameter between 30 and 50 nm were exposed to H2O2 levels between 2 wt% (0.6 M) and 0.007 wt% (2 mM) and a change in hydrodynamic diameter and light intensity scattering was observed, meaning that micelles decompose with elevated concentrations of H2O2. In addition, an increase in hydrodynamic diameter was observed for micelles exposed to a dose between 67 and 500 Gray by irradiating with gamma rays of 1.25 MeV originating from a 60Co source, indicating that micelles cluster after sufficient dose of gamma radiation. These characteristics can be useful for making PDMA-MTPA micelles, a suitable candidate for drug delivery applications.

The entire research described in this thesis is part of the larger field of Systems Chemistry. This field of chemistry deals with the understanding of the complexity of biology by mimicking biochemical reaction networks with emergent properties attributed to the entire system. In particular, this research focuses on the design of artificial non-equilibrium chemical reaction networks (CRNs) inspired by signal transduction pathways in living organisms. Specific attention is given to catalysis in such networks. For the design of the catalytic CRNs, organocatalysts are considered as the ideal candidates as they are simple, cheap, recyclable and robust compared to enzymes and frequently less toxic catalysts than metals. On top of that, since organocatalysts can operate under mild conditions, it can pave the way for future applications in biological environments.

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.

Signal transduction is a rudimentary and specific way of communication in cells, in which a signal triggers a specific response. However, mimicking these processes in organic materials has been a major challenge. Although, some organocatalysts have been shown to be responsive to specific signals, only limited research has been done using organocatalysis in biological systems. A potentially bio-compatible organocatalytic reaction is the DABCO catalysed nucleophilic substitution reaction of a vinylphosphonate with N- and S- terminal nucleophiles. To evaluate the bio-compatibility of the catalytic reaction, this study focused on the preparation of a catalytic active profluorophore. Hereby, the profluorophore becomes active (fluorescent) upon catalysis in the presence of cells. To do so, 7-amino-4-methyl-3-coumarinylacetic acid and 7-amino-1-methylquinolin-1-ium will be synthetically quenched by acetyl amide formation and are thereafter linked to the catalytic active component (3-hydroxyprop-1-en-2-ylphosphonate). Signals, such as amides and thiols can be used to trigger the reaction and hence releasing the quenched fluorophore.

7-amino-4-methyl-3-coumarinylacetic acid was successfully quenched using ethyl chloroformate, however transesterification of the catalytic active compound could not be achieved at various conditions. 7-amino-1-methylquinolin-1-ium was synthesised according to literature and compared to a reference, confirming the compound. Many attempts have been undertaken to further modify the fluorophore with the catalytic compound. Unfortunately, non of the proposed synthetic pathways, such as quenching with ethyl chloroformate, resulted in the envisioned product. Based on the obtained results, it is recommended to explore other synthetic strategies such as the usage of disuccinimidyl carbonate to quench the fluorophores.

Molecular self-assembly has been realized as a powerful approach to control the organization of materials from molecular to macroscopic length scale. While for a long time molecular self-assembly has focused on the investigation of systems involving a single component and under thermodynamic equilibrium. In recent years the interests are shifting towards more complex multicomponent and non-equilibrium self-assembly systems, where the richest functions of the resulted supramolecular objects can be harnessed. In this thesis, multicomponent supramolecular self-assembly and directed molecular self-assembly leading to out-of-equilibrium supramolecular systems are investigated, with the aim to construct new soft functional materials.

Nature is capable of constantly adapting some of its assembled structures in response to external and internal signals. For instance, microtubuli grow and shrink upon cell division and cellular transport. Furthermore, actin fibers play a major role in muscle contraction and cell signaling. To achieve these transient functions, such assembled structures operate in an out-of-equilibrium state. Energy input and dissipation enables structure growth and subsequent collapse. Regulating the energy input with fuel concentration and the activity of associated enzymatically catalyzed processes leads to a high level of kinetic control in biological out-of-equilibrium processes....

Cells react to the environment by changing the activity of enzymes. Catalysts, such as enzymes, speed up reaction rates by lowering the activation energy of the reaction. Changing reaction rates by altering enzyme activity is used to temporarily increase the production of, for instance, a hormone or to change the mechanical properties of a cell. Control over enzyme activity is achieved in two different ways: by covalent modifications (e.g. phosphorylation) and by non-covalent interactions (allosteric enzymes). In this thesis we describe how we designed signal-responsive catalysts and used them to introduce signal response in artificial materials. Inspired by nature we developed a covalent and a noncovalent method to design catalysts that can react to signals from their environment. To design covalently protected catalysts we used self-immolative chemistry. A self-immolative molecule contains a signal-labile functional group. When this group reacts with the signal, the molecule fragments and releases a molecule of interest, in our case a catalyst.