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  1. Clinically serious congenital heart valve defects arise from improper growth and remodeling of endocardial cushions into leaflets. Genetic mutations have been extensively studied but explain less than 20% of cases. Mechanical forces generated by beating hearts drive valve development, but how these forces collectively determine valve growth and remodeling remains incompletely understood. Here, we decouple the influence of those forces on valve size and shape, and study the role of YAP pathway in determining the size and shape. The low oscillatory shear stress promotes YAP nuclear translocation in valvular endothelial cells (VEC), while the high unidirectional shear stress restricts YAP in cytoplasm. The hydrostatic compressive stress activated YAP in valvular interstitial cells (VIC), whereas the tensile stress deactivated YAP. YAP activation by small molecules promoted VIC proliferation and increased valve size. Whereas YAP inhibition enhanced the expression of cell-cell adhesions in VEC and affected valve shape. Finally, left atrial ligation was performed in chick embryonic hearts to manipulate the shear and hydrostatic stress in vivo. The restricted flow in the left ventricle induced a globular and hypoplastic left atrioventricular (AV) valves with an inhibited YAP expression. By contrast, the right AV valves with sustained YAP expression grew and elongated normally. This study establishes a simple yet elegant mechanobiological system by which transduction of local stresses regulates valve growth and remodeling. This system guides leaflets to grow into proper sizes and shapes with the ventricular development, without the need of a genetically prescribed timing mechanism. 
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  2. Load-bearing soft tissues normally show J-shaped stress–strain behaviors with high compliance at low strains yet high strength at high strains. They have high water content but are still tough and durable. By contrast, naturally derived hydrogels are weak and brittle. Although hydrogels prepared from synthetic polymers can be strong and tough, they do not have the desired bioactivity for emerging biomedical applications. Here, we present a thermomechanical approach to replicate the combinational properties of soft tissues in protein-based photocrosslinkable hydrogels. As a demonstration, we create a gelatin methacryloyl fiber hydrogel with soft tissue-like mechanical properties, such as low Young’s modulus (0.1 to 0.3 MPa), high strength (1.1 ± 0.2 MPa), high toughness (9,100 ± 2,200 J/m 3 ), and high fatigue resistance (2,300 ± 500 J/m 2 ). This hydrogel also resembles the biochemical and architectural properties of native extracellular matrix, which enables a fast formation of 3D interconnected cell meshwork inside hydrogels. The fiber architecture also regulates cellular mechanoresponse and supports cell remodeling inside hydrogels. The integration of tissue-like mechanical properties and bioactivity is highly desirable for the next-generation biomaterials and could advance emerging fields such as tissue engineering and regenerative medicine. 
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  3. Abstract

    Load‐bearing soft tissues are soft but strong, strong yet tough. These properties can only be replicated in synthetic hydrogels, which do not have the biocomplexity required by many biomedical applications. By contrast, natural hydrogels, although retaining the native complexity, are weak and fragile. Here a thermomechanical casting method is presented to achieve the mechanical capabilities of synthetic materials in biopolymer hydrogels. The thermomechanical cast and chemically crosslinked biopolymer chains form a short‐range disordered but long‐range ordered structure in water. Upon stretch, the disordered structure transforms to a hierarchically ordered structure. This disorder‐order transformation resembles the synergy of the disordered elastin and ordered collagen in load‐bearing soft tissues. As entropy drives a reverse order‐disorder transformation, the hydrogels can resist repeated cycles of loads without deterioration in mechanical properties. Gelatin hydrogels produced by this method combine tissue‐like tunable mechanical properties that outperform the gelatin prepared by synthetic approaches, and in vivo biocomplexity beyond current natural systems. Unlike polymer engineering approaches, which rely on specific crosslinks provided by special polymers, this strategy utilizes the entropy of swollen chains and is generalizable to many other biopolymers. It could thus significantly accelerate translational success of biomaterials.

     
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  4. Abstract

    The extracellular matrix (ECM) is a complex 3D framework of macromolecules, which regulate cell bioactivity via chemical and physical properties. The ECM's physical properties, including stiffness and physical constraints to cell shape, regulate actomyosin cytoskeleton contractions, which induce signaling cascades influencing gene expression and cell fate. Engineering such bioactivity, a.k.a., mechanotransduction, has been mainly achieved by 2D platforms such as micropatterns. These platforms cause cytoskeletal contractions with apico‐basal polarity and can induce mechanotransduction that is unnatural to most cells in native ECMs. An effective method to engineer mechanotransduction in 3D is needed. This work creates FiberGel, a 3D artificial ECM comprised of sub‐cellular scale fibers. These microfibers can crosslink into defined microstructures with the fibers' diameter, stiffness, and alignment independently tuned. Most importantly, cells are blended amongst the fibers prior to crosslinking, leading to homogeneously cellularized scaffolds. Studies using mesenchymal stem cells showed that the microfibers' diameter, stiffness, and alignment regulate 3D cell shape and the nuclei translocation of transcriptional coactivators YAP/TAZ (yes‐associated protein/transcriptional coactivator), which enables the control of cell differentiation and tissue formation. A novel technology based on repeated stretching and folding is created to synthesize FiberGel. This 3D platform can significantly contribute to mechanotransduction research and applications.

     
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