Abstract
Cell-matrix interactions govern cell behavior and tissue function by facilitating transduction of biomechanical cues. Engineered tissues often incorporate these interactions by employing cell-adhesive materials. However, using constitutively active cell-adhesive materials impedes control over cell fate and elicits inflammatory responses upon implantation. Here, an alternative cell-material interaction strategy that provides mechanotransducive properties via discrete inducible on-cell crosslinking (DOCKING) of materials, including those that are inherently non-cell-adhesive, is introduced. Specifically, tyramine-functionalized materials are tethered to tyrosines that are naturally present in extracellular protein domains via enzyme-mediated oxidative crosslinking. Temporal control over the stiffness of on-cell tethered 3D microniches reveals that DOCKING uniquely enables lineage programming of stem cells by targeting adhesome-related mechanotransduction pathways acting independently of cell volume changes and spreading. In short, DOCKING represents a bioinspired and cytocompatible cell-tethering strategy that offers new routes to study and engineer cell-material interactions, thereby advancing applications ranging from drug delivery, to cell-based therapy, and cultured meat.
Highlights
IntroductionEngineered tissues often incorporate strategies to control cell–biomaterial interthese interactions by employing cell-adhesive materials
As cell–material interactions are instrumental in guiding tissue development, organ homeostasis, disease progression, and repair processes, discrete inducible on-cell crosslinking (DOCKING) represents a unique tool for optimizing tissue engineering applications, such as regenerative medicine, cultured meat, and organ-on-chip platforms
Electrospray ionization mass spectrometry (ESI-MS) confirmed the presence of coupled tyramine–tyramine and tyramine–tyrosine products in the HRP-catalyzed reaction with H2O2 while no crosslinking of tyramine and tyrosine was observed in the absence of H2O2 (Figure 1c)
Summary
Engineered tissues often incorporate strategies to control cell–biomaterial interthese interactions by employing cell-adhesive materials. An alternative cell–material interaction strategy that provides mechanotransducive properties via discrete actions able to transmit mechanical cues from the microenvironment to the cells within engineered tissue constructs has remained limited and near-exclusively relied on cell adhesion. Biomaterials are typically inducible on-cell crosslinking (DOCKING) of materials, including those that endowed with bioligands that bind to cell are inherently non-cell-adhesive, is introduced. DOCKING represents a bioinspired and cytocompatible cell-tethering strategy that offers new routes to study and engineer cell–material interactions, thereby advancing applications ranging from drug delivery, to cell-based therapy, and cultured meat. The constitutively active binding nature of these cell-adhesive bioligands has been associated with adverse effects such as increased fibrous capsule formation and chronic inflammation upon implantation.[8,9] Dynamic material modifi-.
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