Development of Synthetic Platelet‐Activating Hydrogel Matrices to Induce Local Hemostasis

Abstract

Several hemostatic strategies rely on the use of blood components such as fibrinogen and thrombin, which suffer from high cost and short shelf‐life. Here, a cost‐effective synthetic biomaterial is developed for rapid local hemostasis. Instead of using thrombin, thrombin‐receptor‐agonist‐peptide‐6 (TRAP6) is covalently engineered in polyvinyl alcohol (PVA) hydrogels. Soluble PVA‐TRAP6 is first prepared by covalent attachment of cysteine‐containing TRAP6 onto the backbone of PVA‐norbornenes (PVA‐NB) through photoconjugation. Cytotoxicity studies using C2C12 myoblasts indicate that PVA‐NB and PVA‐TRAP6 are nontoxic. Thromboelastography reveals that hemostatic activity of TRAP6 is retained in conjugated form, which is comparable to free TRAP6 solutions with equal concentrations. A 0.1% PVA‐TRAP6 solution can shorten the clotting time (CT) to ca. 45% of the physiological CT. High platelet‐activating efficiency is further confirmed by platelet aggregation assay and flow cytometry (FACS). For potential clinical applications, TRAP6‐presenting hydrogel particulates (PVA‐TRAP6‐P) are developed for local platelet activation and hemostasis. PVA‐TRAP6‐P is prepared by biofunctionalization of photopolymerized PVA‐NB hydrogel particulates (PVA‐NB‐P) with TRAP6. It is demonstrated that PVA‐TRAP6‐P can effectively shorten the CT to ca. 50%. FACS shows that PVA‐TRAP6‐P can activate platelets to a comparable extent as soluble TRAP6 control. Altogether, PVA‐TRAP6‐P represents a promising class of biomaterials for safe hemostasis and wound healing.

Near‐Infrared Light‐Sensitive Polyvinyl Alcohol Hydrogel Photoresist for Spatiotemporal Control of Cell‐Instructive 3D Microenvironments

“…To design a cell‐responsive hydrogel resist, norbornene‐functionalized PVA (nPVA) was selected as gel precursor for several reasons. First, PVA is a commercial water‐soluble synthetic polymer with excellent cytocompatibility .…”

“…First, PVA is a commercial water‐soluble synthetic polymer with excellent cytocompatibility . Second, PVA with hundreds of hydroxyl groups has been modified with a tunable number of norbornene groups for radical thiol–ene photopolymerization . In comparison, existing multiarm PEG macromers can only provide a maximal number of eight groups.…”

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“…To overcome these limitations, several cationic polymers including polylysine, polyornithine, and polyarginine have been reported to accelerate the conversion of fibrinogen to fibrin, and thus stop the bleeding . Recently, the development of hemostatic polymers for platelet aggregation and activation represent an applicable strategy to promote blood coagulation . For example, a block copolymer of poly(lactic‐ co ‐glycolic acid)‐poly‐L‐lysine was synthesized and conjugated with PEG arms to shield the hydrophobic core and increase their circulation time in vivo .…”

“…The resultant nanoparticles were subsequently functionalized with RGD‐containing moieties (e.g., GRGDS), which are able to interact with the activated platelet receptors including glycoprotein IIb‐IIIa and integrin α v β 3 , resulting in the adhesion of platelets and stop internal bleeding via intravenous administration. Alternatively, the hemostatic peptide with a sequence of SFLLRN, also known as thrombin‐receptor‐agonist‐peptide‐6 (TRAP6), was covalently conjugated to the polyvinyl alcohol (PVA) hydrogels ( Figure ) . The TRAP6 ligand was able to interact with the protease‐activated receptor‐1 (PAR‐1) to activate the platelet and accelerate the blood clotting.…”

“…b) Fabrication of TRAP6 functionalized PVA hydrogel for the activation of platelets. Reproduced with permission . Copyright 2015, Wiley‐VCH.…”