Polymeric tissue adhesives provide versatile materials for wound management and are widely used in a variety of medical settings ranging from minor to life-threatening tissue injuries. Compared to the traditional methods of wound closure (i.e., suturing and stapling), they are relatively easy to use, enable rapid application, and introduce minimal tissue damage. Furthermore, they can act as hemostats to control bleeding and provide a tissue-healing environment at the wound site. Despite their numerous current applications, tissue adhesives still face several limitations and unresolved challenges (e.g., weak adhesion strength and poor mechanical properties) that limit their use, leaving ample room for future improvements. Successful development of next-generation adhesives will likely require a holistic understanding of the chemical and physical properties of the tissue-adhesive interface, fundamental mechanisms of tissue adhesion, and requirements for specific clinical applications. In this review, we discuss a set of rational guidelines for design of adhesives, recent progress in the field along with examples of commercially available adhesives and those under development, tissue-specific considerations, and finally potential functions for future adhesives. Advances in tissue adhesives will open new avenues for wound care and potentially provide potent therapeutics for various medical applications.

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Studies of cancer cell migration have found two modes: one that is protease-independent, requiring micron-sized pores or channels for cells to squeeze through, and one that is protease-dependent, relevant for confining nanoporous matrices such as basement membranes (BMs). However, many extracellular matrices exhibit viscoelasticity and mechanical plasticity, irreversibly deforming in response to force, so that pore size may be malleable. Here we report the impact of matrix plasticity on migration. We develop nanoporous and BM ligand-presenting interpenetrating network (IPN) hydrogels in which plasticity could be modulated independent of stiffness. Strikingly, cells in high plasticity IPNs carry out protease-independent migration through the IPNs. Mechanistically, cells in high plasticity IPNs extend invadopodia protrusions to mechanically and plastically open up micron-sized channels and then migrate through them. These findings uncover a new mode of protease-independent migration, in which cells can migrate through confining matrix if it exhibits sufficient mechanical plasticity.

The extracellular matrix (ECM) is a complex assembly of structural proteins that provides physical support and biochemical signaling to cells in tissues. The mechanical properties of the ECM have been found to play a key role in regulating cell behaviors such as differentiation and malignancy. Gels formed from ECM protein biopolymers such as collagen or fibrin are commonly used for 3D cell culture models of tissue. One of the most striking features of these gels is that they exhibit nonlinear elasticity, undergoing strain stiffening. However, these gels are also viscoelastic and exhibit stress relaxation, with the resistance of the gel to a deformation relaxing over time. Recent studies have suggested that cells sense and respond to both nonlinear elasticity and viscoelasticity of ECM, yet little is known about the connection between nonlinear elasticity and viscoelasticity. Here, we report that, as strain is increased, not only do biopolymer gels stiffen but they also exhibit faster stress relaxation, reducing the timescale over which elastic energy is dissipated. This effect is not universal to all biological gels and is mediated through weak cross-links. Mechanistically, computational modeling and atomic force microscopy (AFM) indicate that strain-enhanced stress relaxation of collagen gels arises from force-dependent unbinding of weak bonds between collagen fibers. The broader effect of strain-enhanced stress relaxation is to rapidly diminish strain stiffening over time. These results reveal the interplay between nonlinear elasticity and viscoelasticity in collagen gels, and highlight the complexity of the ECM mechanics that are likely sensed through cellular mechanotransduction.collagen mechanics | viscoelasticity | force-dependent unbinding | biopolymers | stress relaxation T he composition and architecture of ECM is heterogeneous and varies with tissue type and location. One particularly important ECM protein is type Ι collagen, which is the most abundant ECM component and primarily determines the mechanics of connective tissue (1). Type 1 collagen self-assembles into fibers, and these fibers can form networks in vitro. Studies investigating the mechanical properties of collagen networks have revealed that these networks are nonlinearly elastic and exhibit strain stiffening, or an increase in the elasticity as the strain on the network is enhanced (1-3). This nonlinear elasticity is also a characteristic feature of fibrin gels, which serve as the major component of blood clots, as well as in reconstituted networks of intermediate filaments and cytoskeletal actin networks (2, 4-7). These networks are all composed of semiflexible polymers or fibers, which are relatively rigid, so that the tangent to the contour of the polymer is correlated over long lengths, yet undergo substantial bending fluctuations due to thermal energy. Semiflexible polymers or fibers form networks at low volume fractions (8). Strain stiffening in these networks is thought to arise from either the entropic elasticity of single polymers...

Hydrogels are commonly used as artificial extracellular matrices for 3D cell culture and for tissue engineering. Viscoelastic hydrogels with tunable stress relaxation have recently been developed, and stress relaxation in the hydrogels has been found to play a key role in regulating cell behaviors such as differentiation, spreading, and proliferation. Here we report a simple but precise materials approach to tuning stress relaxation of alginate hydrogels with polyethylene glycol (PEG) covalently grafted onto the alginate. Hydrogel relaxation was modulated independent of the initial elastic modulus by varying molecular weight and concentration of PEG along with calcium crosslinking of the alginate. Increased concentration and molecular weight of the PEG resulted in faster stress relaxation, a higher loss modulus, and increased creep. Interestingly, we found that stress relaxation of the hydrogels is determined by the total mass amount of PEG in the hydrogel, and not the molecular weight or concentration of PEG chains alone. We then evaluated the utility of these hydrogels for 3D cell culture. Faster relaxation in RGD-coupled alginate-PEG hydrogels led to increased spreading and proliferation of fibroblasts, and enhanced osteogenic differentiation of mesenchymal stem cells (MSCs). Thus, this work establishes a new materials approach to tuning stress relaxation in alginate hydrogels for 3D cell culture.