Discovery, Investigation, and Implementation of a Photocontrolled Dynamic Covalent Reaction to Reversibly Tune Hydrogel Mechanics.

Accardo, Joseph

doi:https://doi.org/10.21985/n2-16ab-2211

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Discovery, Investigation, and Implementation of a Photocontrolled Dynamic Covalent Reaction to Reversibly Tune Hydrogel Mechanics.

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Part I: Evaluating the relationship between Crosslink Kinetics and Thermodynamics with the hydrogel mechanics. The past two decades have witnessed a surge of applications built upon dynamic covalent chemistry (DCC), both attributed to the scope of developed reactions as well as their modularity.1-3 These reactions have comparable strengths to their static covalent counterparts, but their dynamic exchange allows them to be used for applications traditionally reserved for noncovalent bonds. Such applications include dynamic combinatorial libraries, molecular recognition, self-healing and stimuli-responsive networks, and the construction of 2 and 3-D organic frameworks, among many more.4-5 A emerging application for dynamic covalent reactions is within cross-linked polymer networks. These networks, coined covalent adaptable networks (CANs) are viscoelastic; the dynamic covalent bonds enable properties that resemble both elastic and viscous materials.6 CANs are promising alternatives to permanently crosslinked thermosets and are also commonly found in 3-D cell culture matrixes, shape memory materials, among others. The equilibria and exchange rates of the crosslinks, which directly affect the viscoelasticity of the resulting CAN, are highly sensitive to structural modifications. As such, manipulating crosslink structure and reactivity has become an alternative avenue for chemists to modify network mechanics independently of environmental factors (such as temperature, pH or analytes) or polymer properties (such as architecture, molecular weight, etc.). In this section, I highlight different strategies, whether intentional or serendipitous, to modulate hydrogel mechanics. I discuss how changes in crosslink electronics, connectivity, structure, and steric interactions influence the thermodynamics and/or kinetics of the DCC and the effect of these changes on the hydrogel’s rheological properties, with an emphasis on stiffness and stress-relaxation. Elucidating these relationships will connect the atomic and macroscopic world through physical organic concepts and provide insight for users to design hydrogel networks with desirable properties. The relationship between structure and network reactivity is followed by our investigation on the exchange mechanism of dithiol alkylidenes and their potential as associative crosslinks in aqueous networks. We previously discovered that, when incorporated as crosslinks in silicone vitrimers, dithiol alkylidenes enable stress-relaxation with a rate that is highly dependent upon the structure of the acceptor. In this work, we show that the rate of exchange is dependent upon the structure of the conjugate acceptor. In general, acceptors derived from cyclic diketones and diesters (such as Meldrum’s Acid) react rapidly with thiols, while linear acceptors proceed two to three orders of magnitude slower. A combination of experimental and computational data suggests cyclic diketones exist in a resonance structure which is closer in structure to the transition state of the reaction, consistent with a lower activation energy and rate of reaction. Incorporating various conjugate acceptors as hydrogel crosslinks highlights the delicate relationship between structure and reactivity, where small changes in exchange rate can translate to large changes in network mechanics. Part II. Coupling Photoswitches and Dynamic Covalent Reactions to Reversibly Tune Hydrogel Mechanics. The relationship between crosslink reactivity and hydrogel mechanics may be harnessed to design stimuli responsive biomaterials. Photochemical reactions have been employed to tune network mechanics for a variety of applications, from cell culture to drug discovery, and benefit from the spatiotemporal control offered by light as an external stimulus.7 Many of the photochemical reactions employed operate unidirectionally, such that light-triggered changes are irreversible. In this work, we introduce new concepts to control network reactivity with light. Specifically, we couple an azobenzene photoswitch to a dynamic covalent boronic ester bond to reversibly tune bond formation and rupture. A combination of experimental and computational data suggests that intramolecular hydrogen bond formation between the E azobenzenes and the boronic acid disfavor esterification. Irradiation of the E isomer from the Z isomer both eliminates the stabilization effect and decreases steric hinderance. Both of these factors make esterification more favorable for the Z isomer. The azobenzene isomerization is reversible with an appropriate wavelength of light, meaning that either the E or Z isomer can be favored, and thus the position of the boronic acid-ester equilibrium can be photochemically controlled. Coupling the azobenzenes to star poly(ethylene glycol) polymers and mixing with sugar capped polymers results in the formation of a hydrogel where the stiffness can be controlled by E to Z isomerization. Rheological characterization reveals that the hydrogels are viscoelastic, exhibiting stress relaxation on the order of seconds which is insensitive to isomerization. These results allow us to decouple stiffness and stress-relaxation effects when using these hydrogels as cell-culture scaffolds, unlocking new avenues for understanding mechanotransduction.

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