Presented here is a cytocompatible covalently adaptable hydrogel uniquely capable of mimicking the complex biophysical properties of native tissue and enabling natural cell functions without matrix degradation. Demonstrated is both the ability to control elastic modulus and stress relaxation time constants by more than an order of magnitude while predicting these values based on fundamental theoretical understanding and the simulation of muscle tissue and the encapsulation of myoblasts.

Rheological and small molecule kinetic studies were performed to study the formation and hydrolysis of the bis-aliphatic hydrazone bond. The rate of gelation was found to correspond closely with the rate of bond formation and the rate of gel relaxation with the rate of hydrolysis, indicating that small molecule kinetic studies can play an important role in material design. Furthermore, unlike aryl or acyl hydrazone bonds, the bis-aliphatic hydrazone bond forms rapidly under physiological conditions without requiring aniline catalysis yet maintains a pH-dependent rate of hydrolysis. These results suggest the bis-aliphatic hydrazone bond should find use alongside existing bioorthogonal click chemistries for bioconjugation, biomaterial synthesis, and controlled release applications.

The design, synthesis, and characterization of a new class of coumarin-based photodegradable hydrogels are reported. Hydrogel formation was achieved rapidly and efficiently under aqueous conditions using copper-catalyzed click chemistry, which afforded excellent control over the rate of network formation. Rapid photodegradation, to the point of reverse gelation, was observed using both 365 and 405 nm light, and micrometer-scale features were eroded using two-photon irradiation at wavelengths as long as 860 nm.

A covalently adaptable hydrazone-crosslinked PEG hydrogel is used to measure the force of extension exerted by motor neurites.

Hydrogels with photocleavable units incorporated into the cross-links have provided researchers with the ability to control mechanical properties temporally and study the role of matrix signaling on stem cell function and fate. With a growing interest in dynamically tunable cell culture systems, methods to synthesize photolabile hydrogels from simple precursors would facilitate broader accessibility. Here, a step-growth photodegradable poly(ethylene glycol) (PEG) hydrogel system cross-linked through a strain promoted alkyne-azide cycloaddition (SPAAC) reaction and degraded through the cleavage of a nitrobenzyl ether moiety integrated into the cross-links is developed from commercially available precursors in three straightforward synthetic steps with high yields (>95%). The network evolution and degradation properties are characterized in response to one-and two-photon irradiation. The PEG hydrogel is employed to encapsulate embryonic stem cell-derived motor neurons (ESMNs), and in situ degradation is exploited to gain three-dimensional control over the extension of motor axons using two-photon infrared light. Finally, ESMNs and their in vivo synaptic partners, myotubes, are coencapsulated, and the formation of user-directed neural networks is demonstrated.

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A cell stressing a hydrazone‐crosslinked, step‐growth covalently adaptable poly(ethylene) glycol polymer network is shown in the image. Because of the dynamic nature of the hydrazone bonds, the stressed crosslinks yield to the forces applied by the cytoskeleton, allowing the cell to spread without perturbing the biophysical properties of the cellular microenvironment, as shown by Kristi S. Anseth and co‐workers on page 865.