Engineered Molecular Therapeutics Targeting Fibrin and the Coagulation System: a Biophysical Perspective.

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.

Autonomously Self-Adhesive Hydrogels as Building Blocks for Additive Manufacturing.

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.

Tuning the properties of injectable poly(oligoethylene glycol methacrylate) hydrogels by controlling precursor polymer molecular weight.

Tuning the properties of in situ-gelling injectable hydrogels based on synthetic polymers typically involves changing the chemistry of polymer backbones or the density of reactive functional groups on precursor polymers. Herein, we describe injectable, hydrazone crosslinked hydrogels based on well-defined poly(oligoethylene glycol methacrylate) (POEGMA) precursors prepared via reversible addition-fragmentation chain transfer (RAFT). These hydrogels have different molecular weights but similar functional group content, enabling engineering of hydrogel properties without substantially changing the chemistry of the precursor polymer. Specifically, although the number of functional crosslinks formed in each gel was found to be equivalent, hydrogels prepared with higher molecular weight precursor polymers showed faster gelation times, higher compressive and shear moduli, slower degradation, and less swelling than gels prepared with lower molecular weight precursor polymers. Thus, this approach is particularly attractive in cases in which separating the effects of physical and chemical changes to gel substrates is critical to understanding or controlling underlying biological interactions.