An antithrombotic hydrogel with thrombin-responsive fibrinolytic activity: breaking down the clot as it forms

Du, Hui; Liu, Cong; Luan, Yuxia; Liu, Qi; Yang, Weikang; Yu, Qian; Li, Dan; Brash, John L.; Chen, Hong

doi:10.1039/c6mh00307a

Cited by 37 publications

(23 citation statements)

References 47 publications

(48 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To eliminate the effect of thrombin during clot formation, the lysis of an existing clot was tested using an agarose plate assay . Briefly, an agarose plate was impregnated with fibrin such that the clot was self‐supporting and clot lysis could be observed as the change in light transmission through the plate.…”

Section: Resultsmentioning

confidence: 99%

“…Zhang et al applied similar hydrogel system to a transcutaneous patch for auto‐anticoagulant regulation . Also we previously developed a thrombin‐responsive fibrinolytic hydrogel which can break down fibrin as it forms . However, these preliminary work involved only bulk hydrogels which are not applicable to the existing blood‐contacting devices.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Thrombosis‐Responsive Thrombolytic Coating Based on Thrombin‐Degradable Tissue Plasminogen Activator (t‐PA) Nanocapsules

Liu

Yang

et al. 2017

Adv Funct Materials

Self Cite

View full text Add to dashboard Cite

Surface modification with bioactive agents capable of combating thrombosis is a widely used strategy for developing antithrombotic biomaterials. However, exposure of the blood to the antithrombotic agent on the material surface may cause hemostatic disorders under normal conditions. Ideally an implanted biomaterial should respond appropriately on demand to a specific change in the physiologic environment, as happens in the body itself. In the present study, a thrombosis-responsive surface coating with the ability to lyse fibrin as it forms is reported. The coating consists of nanocapsules (NCs) in which the fibrinolysis activator t-PA is encapsulated in a thrombin-degradable hydrogel shell. The t-PA NCs are attached to several materials covalently through a polydopamine adhesive layer. The resulting surfaces are treated with the antifouling agent glutathione (GSH) to prevent further interactions with blood/plasma components. The t-PA NCs/GSHcoated surface is stable and remain inert in normal plasma environment while releasing t-PA and promoting fibrinolysis when thrombin is present. The fibrinolytic activity increases with increasing thrombin concentration, and therefore presumably with the extent of thrombosis. This work constitutes the first report of an antithrombotic coating whose function is triggered and regulated, respectively, by the appearance of thrombin and the extent of coagulation.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Thrombosis‐Responsive Thrombolytic Coating Based on Thrombin‐Degradable Tissue Plasminogen Activator (t‐PA) Nanocapsules

Liu

Yang

et al. 2017

Adv Funct Materials

Self Cite

View full text Add to dashboard Cite

show abstract

“…thrombus-activated delivery strategies in response to factors present in the characteristic microenvironment of a thrombus site, such as thrombin [24,25], fibrin network [26,27], collagen [28], glycoprotein [29] and P-selectin [30][31][32], provide a new perspective for the design of clot-specific therapeutics. Among these, upregulation of GPIIb-IIIa (α IIb β 3 ) integrin on activated platelets has been described as a significant hallmark of thrombus, because α IIb β 3…”

Section: Accepted Manuscriptmentioning

confidence: 99%

An activated-platelet-sensitive nanocarrier enables targeted delivery of tissue plasminogen activator for effective thrombolytic therapy

Huang

Ren

et al. 2019

Journal of Controlled Release

View full text Add to dashboard Cite

It remains a major challenge to develop a selective and effective fibrinolytic system for thrombolysis with minimal undesirable side effects. Herein, we report a multifunctional liposomal system (164.6 ± 5.3 nm in diameter) for selective thrombolysis through targeted delivery and controlled release of tissue plasminogen activator (tPA) at the thrombus site. The tPA-loaded liposomes were PEGylated to improve their stability, and surface coated with a conformationally-constrained, cyclic arginine-glycine-aspartic acid (cRGD) to enable highly selective binding to activated platelets. The in vitro drug release profiles at 37 o C showed that over 90% of tPA was released through liposomal membrane destabilization involving membrane fusion upon incubation with activated platelets within 1 h, whereas passive release of the encapsulated tPA in pH 7.4 PBS buffer was 10% after 6 h. The release of tPA could be readily manipulated by changing the concentration of activated platelets. The presence of activated platelets enabled the tPA-loaded, cRGD-coated, PEGylated liposomes to induce efficient fibrin clot lysis in a fibrin-agar plate model and the encapsulated tPA retained 97.4 ± 1.7% of fibrinolytic activity as compared with that of native tPA. Furthermore, almost complete blood clot lysis was achieved in 75 min, showing considerably higher and quicker thrombolytic activity compared to the tPA-loaded liposomes without cRGD labelling. These results suggest that the nano-sized, activated-platelet-sensitive, multifunctional liposomes could facilitate selective delivery and effective release of tPA at the site of thrombus, thus achieving efficient clot dissolution whilst minimising undesirable side effects.

show abstract

“…[127] A thrombin-responsive fibrinolytic hydrogel has been developed to break down fibrin as it forms. [128] The thrombolytic agent tissue plasminogen activator (t-PA) was entrapped in the hydrogel and released while the gel was degraded by elevated thrombin during coagulation. Importantly, the t-PA-releasing hydrogel was able to lyse fibrin by converting plasminogen into plasmin, which is responsible for fibrin degradation in the presence of thrombin, indicating thrombosis-responsive fibrinolytic properties.…”

Section: Environment-responsive Hydrogelmentioning

confidence: 99%

Biomaterials Regulating Bone Hematoma for Osteogenesis

Yang

Xiao

2020

Adv Healthcare Materials

View full text Add to dashboard Cite

Blood coagulation in tissue healing not only prevents blood loss, but also forms a natural scaffold for tissue repair and regeneration. As blood clot formation is the initial and foremost phase upon bone injury, and the quality of blood clot (hematoma) orchestrates the following inflammatory and cellular processes as well as the subsequent callus formation and bone remodeling process. Inspired by the natural healing hematoma, tissue-engineered biomimic scaffold/hydrogels and blood prefabrication strategies attract significant interests in developing functional bone substitutes. The alteration of the fracture hematoma ca significantly accelerate or impair the overall bone healing process. This review summarizes the impact of biomaterials on blood coagulation and provides evidence on fibrin network structure, growth factors, and biomolecules that contribute to bone healing within the hematoma. The aim is to provide insights into the development of novel implant and bone biomaterials for enhanced osteogenesis. Advances in the understanding of biomaterial characteristics (e.g., morphology, chemistry, wettability, and protein adsorption) and their effect on hematoma properties are highlighted. Emphasizing the importance of the initial healing phase of the hematoma endows the design of advanced biomaterials with the desired regulatory properties for optimal coagulation and hematoma properties, thereby facilitating enhanced osteogenesis and ideal therapeutic effects.

show abstract

An antithrombotic hydrogel with thrombin-responsive fibrinolytic activity: breaking down the clot as it forms

Abstract: A novel concept of a thrombolytic material whose activity is triggered by the generation of a clot/thrombus is developed.

Cited by 37 publications

References 47 publications

Thrombosis‐Responsive Thrombolytic Coating Based on Thrombin‐Degradable Tissue Plasminogen Activator (t‐PA) Nanocapsules

Thrombosis‐Responsive Thrombolytic Coating Based on Thrombin‐Degradable Tissue Plasminogen Activator (t‐PA) Nanocapsules

An activated-platelet-sensitive nanocarrier enables targeted delivery of tissue plasminogen activator for effective thrombolytic therapy

Biomaterials Regulating Bone Hematoma for Osteogenesis

Contact Info

Product

Resources

About