Graphical Abstract
This review highlights recent efforts in using photochemistry to exert dynamic control over the properties of hydrogel biomaterials.
Hydrogels with tunable viscoelasticity hold promise as materials that can recapitulate many dynamic mechanical properties found in native tissues. Here, covalent adaptable boronate bonds are exploited to prepare hydrogels that exhibit fast relaxation, with relaxation time constants on the order of seconds or less, but are stable for long‐term cell culture and are cytocompatible for 3D cell encapsulation. Using human mesenchymal stem cells (hMSC) as a model, the fast relaxation matrix mechanics are found to promote cell–matrix interactions, leading to spreading and an increase in nuclear volume, and induce yes‐associated protein/PDZ binding domain nuclear localization at longer times. All of these effects are exclusively based on the hMSCs' ability to physically remodel their surrounding microenvironment. Given the increasingly recognized importance of viscoelasticity in controlling cell function and fate, it is expected that the synthetic strategies and material platform presented should provide a useful system to study mechanotransduction on and within viscoelastic environments and explore many questions related to matrix biology.
Bone marrow derived human mesenchymal stem cells (hMSCs) are a promising cell source for regenerative therapies; however, ex vivo expansion is often required to achieve clinically useful cells numbers. Recent results reveal that when MSCs are cultured in stiff microenvironments, their regenerative capacity can be altered in a manner that is dependent on time (e.g., a mechanical dosing analogous to a chemical one). It is hypothesized that epigenomic modifications are involved in storing these mechanical cues, regulating gene expression, and ultimately leading to a mechanical memory. Using hydrogels containing an allyl sulfide cross‐linker and a radical‐mediated addition‐fragmentation chain transfer process, in situ softened hMSC‐laden hydrogels at different time points are achieved and the effects of short‐term and long‐term mechanical dosing on epigenetic modifications in hMSCs are quantified. Results show that histone acetylation and chromatin organization adapt rapidly after softening and can be reversible or irreversible depending on time of exposure to stiff microenvironments. Furthermore, epigenetic modulators are differentially expressed depending on the culture history. Collectively, these experiments suggest that epigenetic remodeling can be persistent and might be a memory keeper.
At its basic conceptualization, photoclick
chemistry embodies a
collection of click reactions that are performed via the application
of light. The emergence of this concept has had diverse impact over
a broad range of chemical and biological research due to the spatiotemporal
control, high selectivity, and excellent product yields afforded by
the combination of light and click chemistry. While the reactions
designated as “photoclick” have many important features
in common, each has its own particular combination of advantages and
shortcomings. A more extensive realization of the potential of this
chemistry requires a broader understanding of the physical and chemical
characteristics of the specific reactions. This review discusses the
features of the most frequently employed photoclick reactions reported
in the literature: photomediated azide–alkyne cycloadditions,
other 1,3-dipolarcycloadditions, Diels–Alder and inverse electron
demand Diels–Alder additions, radical alternating addition
chain transfer additions, and nucleophilic additions. Applications
of these reactions in a variety of chemical syntheses, materials chemistry,
and biological contexts are surveyed, with particular attention paid
to the respective strengths and limitations of each reaction and how
that reaction benefits from its combination with light. Finally, challenges
to broader employment of these reactions are discussed, along with
strategies and opportunities to mitigate such obstacles.
There is ag rowing interest in materials that can dynamically change their properties in the presence of cells to study mechanobiology.H erein, we exploit the 365 nm light mediated [4+ +4] photodimerization of anthracene groups to develop cytocompatible PEG-based hydrogels with tailorable initial moduli that can be further stiffened. Ah ydrogel formulation that can stiffen from 10 to 50 kPa, corresponding to the stiffness of ahealthy and fibrotic heart, respectively,was prepared. This system was used to monitor the stiffnessdependent localization of NFAT,adownstream target of intracellular calcium signaling using ar eporter in live cardiac fibroblasts (CFbs). NFAT translocates to the nucleus of CFbs on stiffening hydrogels within 6h,w hereas it remains cytoplasmic when the CFbs are cultured on either 10 or 50 kPa static hydrogels.T his finding demonstrates howd ynamic changes in the mechanical properties of am aterial can reveal the kinetics of mechanoresponsive cell signaling pathwaysthat may otherwise be missed in cells cultured on static substrates.
Intestinal organoid protocols rely on the use of extracellular scaffolds, typically Matrigel, and upon switching from growth to differentiation promoting media, a symmetry breaking event takes place. During this stage, the first bud like structures analogous to crypts protrude from the central body and differentiation ensues. While organoids provide unparalleled architectural and functional complexity, this sophistication is also responsible for the high variability and lack of reproducibility of uniform crypt‐villus structures. If function follows form in organoids, such structural variability carries potential limitations for translational applications (e.g., drug screening). Consequently, there is interest in developing synthetic biomaterials to direct organoid growth and differentiation. It has been hypothesized that synthetic scaffold softening is necessary for crypt development, and these mechanical requirements raise the question, what compressive forces and subsequent relaxation are necessary for organoid maturation? To that end, allyl sulfide hydrogels are employed as a synthetic extracellular matrix mimic, but with photocleavable bonds that temporally regulate the material's bulk modulus. By varying the extent of matrix softening, it is demonstrated that crypt formation, size, and number per colony are functions of matrix softening. An understanding of the mechanical dependence of crypt architecture is necessary to instruct homogenous, reproducible organoids for clinical applications.
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