Synthetic Platelet Microgels Containing Fibrin Knob B Mimetic Motifs Enhance Clotting Responses
Synthetic Platelet Microgels Containing Fibrin Knob B Mimetic Motifs Enhance Clotting Responses
复制标题
DOI：
10.1002/adtp.202100010
复制
发表时间：
2021-03
影响因子：
4.6
通讯作者：
Seema Nandi;Emily P. Mihalko;K. Nellenbach;Mario Castaneda;John D Schneible;Mary G Harp;Halston Deal;M. Daniele;S. Menegatti;T. Barker;Ashley C. Brown
中科院分区：
文献类型：
--
作者：
Seema Nandi;Emily P. Mihalko;K. Nellenbach;Mario Castaneda;John D Schneible;Mary G Harp;Halston Deal;M. Daniele;S. Menegatti;T. Barker;Ashley C. Brown
天然血小板在伤口愈合中起着至关重要的作用。其作用的关键是其表面受体GPIIb/IIIa在损伤部位结合纤维蛋白的能力，从而促进凝血。当血小板活性由于创伤性损伤或某些疾病而受损时，可能导致不受控制的出血。为了在血小板活性差的情况下帮助凝血和组织修复，先前已经在实验室中开发了能够促进凝血和改善伤口愈合反应的合成血小板样颗粒。这些通过用纤维蛋白结合配体（包括纤维蛋白特异性全抗体或单结构域可变片段）功能化高度可变形的水凝胶微粒（微凝胶）来构建。为了提高这些凝血材料的翻译潜力，探索了使用纤维蛋白结合肽作为抗体的具有成本效益的、稳健的、高特异性的替代品。在此，提出了用肽AHRPYAAK修饰的软微凝胶的开发和表征，肽AHRPYAAK模拟纤维蛋白结“B”并靶向纤维蛋白孔“B”。发现这些“具有凝血产率的纤维蛋白-亲和微凝胶”（FAMCY）在体外显著增加凝块密度，并在体内啮齿动物创伤模型中减少出血。这些结果表明，FAMCY能够重现先前设计的血小板模拟特性，同时利用成本更低、更具平移性的设计。
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.