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Hydrogels constructed with functionalized polysaccharides are of interest in a multitude of applications, chiefly the design of therapeutic and regenerative formulations. Tailoring the chemical modification of polysaccharide-based hydrogels to achieve specific drug release properties involves the optimization of many tunable parameters, including (i) the type, degree ( χ ), and pattern of the functional groups, (ii) the water–polymer ratio, and (iii) the drug payload. To guide the design of modified polysaccharide hydrogels for drug release, we have developed a computational toolbox that predicts the structure and physicochemical properties of acylated chitosan chains, and their impact on the transport of drug molecules. Herein, we present a multiscale coarse-grained model to investigate the structure of networks of chitosan chains modified with acetyl, butanoyl, or heptanoyl moieties, as well as the diffusion of drugs doxorubicin (Dox) and gemcitabine (Gem) through the resulting networks. The model predicts the formation of different network structures, in particular the hydrophobically-driven transition from a uniform to a cluster/channel morphology and the formation of fibers of chitin chains. The model also describes the impact of structural and physicochemical properties on drug transport, which was confirmed experimentally by measuring Dox and Gem diffusion through an ensemble of modified chitosan hydrogels. 

The impact of next-generation biorecognition elements (ligands) will be determined by the ability to remotely control their binding activity for a target biomolecule in complex environments. Compared to conventional mechanisms for regulating binding affinity (pH, ionic strength, or chaotropic agents), light provides higher accuracy and rapidity, and is particularly suited for labile targets. In this study, we demonstrate a general method to develop azobenzene-cyclized peptide ligands with light-controlled affinity for target proteins. Light triggers a cis/trans isomerization of the azobenzene, which results in a major structural rearrangement of the cyclic peptide from a non-binding to a binding configuration. Critical to this goal are the abiliy to achieve efficient photo-isomerization under low light dosage and the temporal stability of both cis and trans isomers. We demonstrated our method by designing photo-switchable peptides targeting vascular cell adhesion marker 1 (VCAM1), a cell marker implicated in stem cell function. Starting from a known VCAM1-binding linear peptide, an ensemble of azobenzene-cyclized variants with selective light-controlled binding were identified by combining in silico design with experimental characterization via spectroscopy and surface plasmon resonance. Variant cycloAZOB[G-VHAKQHRN-K] featured rapid, light-controlled binding of VCAM1 (KD,Trans/KD,Cis ~ 130). Biotin-cycloAZOB[G-VHAKQHRN-K] was utilized to label brain microvascular endothelial cells (BMECs), showing co-localization with anti-VCAM1 antibodies in cis configuration and negligible binding in trans configuration. 

Abstract Native platelets are crucial players in wound healing. Key to their role is the ability of their surface receptor GPIIb/IIIa to bind fibrin at injury sites, thereby promoting clotting. When platelet activity is impaired as a result of traumatic injury or certain diseases, uncontrolled bleeding can result. To aid clotting and tissue repair in cases of poor platelet activity, synthetic platelet‐like particles capable of promoting clotting and improving wound healing responses have been previously developed in the lab. These are constructed by functionalizing highly deformable hydrogel microparticles (microgels) with fibrin‐binding ligands including a fibrin‐specific whole antibody or a single‐domain variable fragment. To improve the translational potential of these clotting materials, the use of fibrin‐binding peptides as cost‐effective, robust, high‐specificity alternatives to antibodies are explored. Herein, the development and characterization of soft microgels decorated with the peptide AHRPYAAK that mimics fibrin knob “B” and targets fibrin hole “b” are presented. These “fibrin‐affine microgels with clotting yield” (FAMCY) are found to significantly increase clot density in vitro and decrease bleeding in a rodent trauma model in vivo. These results indicate that FAMCYs are capable of recapitulating the platelet‐mimetic properties of previous designs while utilizing a less costly, more translational design.