Synthetic Platelet Microgels Containing Fibrin Knob B Mimetic Motifs Enhance Clotting Responses

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.

Recent Advances in Blood Cell-Inspired and Clot-Targeted Thrombolytic Therapies

“…Te fbrin-binding ability allows PLP to bind to fbrin at injury sites. We have shown in rodent trauma models that following intravenous injection, PLPs target wound sites and interface with nascent fbrin fbers to augment clotting and decrease bleeding in vivo [50,52]. We have also demonstrated that PLPs mimic platelet-mediated clot retraction, a function which stabilizes clots and promotes long term healing responses.…”

Bioactive Hydrogels with Pro‐coagulation Effect for Hemostasis†

“…Platelets can also be captured and enriched using polyphenols, [ 195 ] keratin, [ 196 ] and other materials. [ 197 ] In addition to directly capturing platelets, hemostasis can be achieved by activating platelet receptors using peptides [ 158‐159 ] or designing platelet‐mimicking materials [ 198 ] to enhance or mimic platelet function. However, these hydrogels that absorb, capture, enrich, and activate platelets can only play a passive hemostatic function.…”

Biomaterials for treating sepsis-induced thromboinflammation

“…In this case, the lack of platelet availability from which to derive membranes was the primary obstacle (Raghunathan et al, 2022). To overcome the challenge of platelet membrane availability, some research groups coat nanoparticles with hemostatic proteins found on platelets, including fibrin knob B (Nandi et al, 2021), fibrin antibodies (Brown et al, 2014), phosphatidylserine (Sekhon et al, 2022), vWF-binding peptides, and collagen-binding peptides (Gao et al, 2020;Girish et al, 2022;Gao et al, 2023) (Table 2). These platelet-mimicking particles promote clotting, reduce blood loss, and decrease bleeding time in various models, including liver laceration, tail-clip injury, hemophilia, and human plasma from patients with coagulopathy.…”