We report a simple method of preparing autonomous and rapid self-adhesive hydrogels and their use as building blocks for additive manufacturing of functional tissue scaffolds. Dynamic cross-linking between 2-aminophenylboronic acid-functionalized hyaluronic acid and poly(vinyl alcohol) yields hydrogels that recover their mechanical integrity within 1 min after cutting or shear under both neutral and acidic pH conditions. Incorporation of this hydrogel in an interpenetrating calcium-alginate network results in an interfacially stiffer but still rapidly self-adhesive hydrogel that can be assembled into hollow perfusion channels by simple contact additive manufacturing within minutes. Such channels withstand fluid perfusion while retaining their dimensions and support endothelial cell growth and proliferation, providing a simple and modular route to produce customized cell scaffolds.
Fibrin (Fb) networks self‐assemble through the coagulation cascade and serve as the structural foundation of blood clots. Following severe trauma or drug therapy, reduced integrity of Fb networks can lead to formation of clots with inadequate mechanical properties. A key feature of therapeutic interventions for hemostasis is therefore the ability to restore mechanical strength to clots formed under coagulopathic conditions. Here, an intrinsically disordered protein based on an elastin‐like polypeptide (ELP) sequence is described, which specifically binds Fb and modulates its mechanical properties. Hemostatic ELPs (hELPs) are designed containing N‐ and C‐terminal peptide tags that are selectivity recognized by human transglutaminase factor XIIIa and covalently linked into fibrin networks via the natural coagulation cascade. Phase separation of hELPs above their lower critical solution temperature leads to stiffening and rescue of clot biophysical properties under simulated conditions of dilutive coagulopathy. In addition to phase‐dependent stiffening, the resulting hELP‐Fb networks exhibit resistance to plasmin degradation, reduced pore sizes, and accelerated gelation rate following initiation of clotting. These results demonstrate the ability of protein‐based phase separation to modulate the physical and biochemical properties of blood clots and suggest protein phase separation as a new mechanism for achieving hemostasis in clinical settings.
The coagulation cascade represents a sophisticated and highly choreographed series of molecular events taking place in the blood with important clinical implications. One key player in coagulation is fibrinogen, a highly abundant soluble blood protein that is processed by thrombin proteases at wound sites, triggering self-assembly of an insoluble protein hydrogel known as a fibrin clot. By forming the key protein component of blood clots, fibrin acts as a structural biomaterial with biophysical properties well suited to its role inhibiting fluid flow and maintaining hemostasis. Based on its clinical importance, fibrin is being investigated as a potentially valuable molecular target in the development of coagulation therapies. In this topical review, we summarize our current understanding of the coagulation cascade from a molecular, structural and biophysical perspective. We highlight single-molecule studies on proteins involved in blood coagulation and report on the current state of the art in directed evolution and molecular engineering of fibrin-targeted proteins and polymers for modulating coagulation. This biophysical overview will help acclimatize newcomers to the field and catalyze interdisciplinary work in biomolecular engineering toward the development of new therapies targeting fibrin and the coagulation system.
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