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首页> 外文会议>World biomaterials congress >Polymerization of PEG in blood plasma by coagulation factor (ⅩⅢ)a exhibits a spatially-propagating front and increases the adhesion of clots
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Polymerization of PEG in blood plasma by coagulation factor (ⅩⅢ)a exhibits a spatially-propagating front and increases the adhesion of clots

机译：凝血因子（ⅩⅢ）a在血浆中PEG的聚合表现出空间传播的前沿并增加了血凝块的粘附

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Introduction: Despite an increasing number of hemostatic agents available, bleeding still accounts for roughly half of all trauma deaths in hospitals. The natural coagulation system is usually effective at halting moderate bleeding, and thus creating new materials that mimic fibrin may lead to new hemostatic agents. Unique properties of fibrin include its ability to polymerize as a propagating reactive frontl, and its strong adhesion to injured tissues, which is catalyzed by the transglutaminase coagulation factor (ⅩⅢ)a (F(ⅩⅢ)a). We hypothesized that adding a F(ⅩⅢ)a-crosslinkable material to clots would make them more adhesive. Here, we show that a well-characterized F(ⅩⅢ)a-crosslinkable material can mimic fibrin to polymerize by spatial propagation and increase clot adhesion. Materials and Methods: A glutamine-donating peptide substrate of F(ⅩⅢ)a was conjugated to PEG (GIn-PEG) and formulated with an amine-donor, spermidine, in plasma as described. To measure frontal propagation, this mixture was flowed into tissue factor(TF)-pattemed microfluidic channels and polymerization was traced by time-lapse microscopy. To measure adhesion, a mix containing normal plasma (36%v/v), GIn-PEG (44mg/mL), spermidine (1.2mM), CaCl2 (4.8mM), NaCl (11mM), purified F(ⅩⅢ) (0.18mg/mL), and APTT activator (2.4% v/v) was clotted between glass substrates. A lap-shear test was done using a mechanical analyzer (TA Q800). Results and Discussion: The self-assembly and polymerization of fibrin during clotting is a rare example of frontal polymerization in nature, where gelation spatially propagates as a reactive front. To test whether a F(ⅩⅢ)a-crosslinkable synthetic material could mimic frontal polymerization of fibrin clots without flow, GIn-PEG and spermidine were added to fibrinogen(Fg)-deficient plasma in a microfluidic channel patterned with clot activator, TF (Fig.1A-E). Polymerization initiated at TF then propagated through stagnant plasma (32m/min, Fig.1F) similar to Fg-rich clots (21 m/min, Fig.1G). In contrast, when preactivated F(ⅩⅢ)a was added to GIn-PEG-spermidine, polymerization was uniform and did not propagate. This shows that frontal polymerization in coagulation is dependent on the coagulation cascade, and a F(ⅩⅢ)a-crosslinkable synthetic material can mimic this unique polymerization property of fibrin. To test if adding a F(ⅩⅢ)a-crosslinkable material makes clots more adhesive, GIn-PEG and spermidine were added to plasma and the composite clot's adhesion was measured in a lap-shear test. Shear strength increased from 1.3kPa to 5.6kPa. This shows a F(ⅩⅢ)a-crosslinkable synthetic material can supplement Fg to increase clot adhesion. Conclusion: Coupling the polymerization of a synthetic material to the coagulation cascade allows it to mimic fibrin's ability to form and adhere in response to signals of vascular injury. This strategy may be useful for developing novel hemostatic materials.
机译：简介：尽管止血剂的使用量不断增加，但出血仍约占医院所有创伤死亡人数的一半。天然凝血系统通常可有效阻止中度出血，从而创造出模仿纤维蛋白的新物质，可能会导致新的止血剂。纤维蛋白的独特性质包括其作为传播的反应性前锋聚合的能力，以及对受损组织的强粘附力，这是由转谷氨酰胺酶凝血因子（ⅩⅢ）a（F（ⅩⅢ）a）催化的。我们假设在凝块中添加可与F（）Ⅲ）a交联的材料会使它们更具粘性。在这里，我们表明，特征明确的F（ⅩⅢ）a可交联材料可以通过空间传播模拟纤维蛋白聚合并增加血凝块粘附。材料和方法：将F（Ⅲ）a的谷氨酰胺供体肽底物与PEG（GIn-PEG）偶联，并按所述方法在血浆中与胺供体亚精胺一起配制。为了测量额叶的传播，将该混合物流入组织因子（TF）模式的微流体通道，并通过延时显微镜对聚合反应进行追踪。为了测量粘附力，应使用含有正常血浆（36％v / v），GIn-PEG（44mg / mL），亚精胺（1.2mM），CaCl2（4.8mM），NaCl（11mM），纯化的F（ⅩⅢ）（0.18）的混合物毫克/毫升）和APTT活化剂（2.4％v / v）凝结在玻璃基板之间。使用机械分析仪（TA Q800）进行搭接剪切测试。结果与讨论：凝结过程中纤维蛋白的自组装和聚合是自然界中额叶聚合的罕见例子，其中胶凝作用在空间上以反应前沿的形式传播。为了测试F（ⅩⅢ）a可交联的合成材料是否可以模拟血纤维蛋白凝块的额聚反应而没有流动，将GIn-PEG和亚精胺添加到血纤维蛋白原（Fg）缺乏的血浆中，该血流通道具有血凝激活剂TF（图2）。 .1A-E）。聚合反应在TF开始，然后通过停滞的血浆（32m / min，图1F）传播，类似于富含Fg的血块（21 m / min，图1G）。相反，当将预活化的F（ⅩⅢ）a添加到GIn-PEG-亚精胺中时，聚合反应是均匀的，不会扩散。这表明凝结中的前沿聚合反应取决于凝结级联反应，并且可与F（ⅩⅢ）a交联的合成材料可以模仿血纤蛋白的这种独特的聚合特性。为了测试是否添加F（ⅩⅢ）a可交联材料使血凝块具有更大的粘附性，将GIn-PEG和亚精胺添加到血浆中，并在搭接剪切试验中测量了复合血凝块的粘附性。剪切强度从1.3kPa增加到5.6kPa。这表明F（ⅩⅢ）a可交联的合成材料可以补充Fg以增加血凝块粘附力。结论：将合成材料的聚合反应耦合至凝血级联反应，使其能够模拟纤维蛋白响应血管损伤信号而形成和粘附的能力。该策略对于开发新型止血材料可能有用。

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