Bio-responsive polymer hydrogels homeostatically regulate blood coagulation

Abstract

Bio-responsive polymer architectures can empower medical therapies by engaging molecular feedback-response mechanisms resembling the homeostatic adaptation of living tissues to varying environmental constraints. Here we show that a blood coagulation-responsive hydrogel system can deliver heparin in amounts triggered by the environmental levels of thrombin, the key enzyme of the coagulation cascade, which—in turn—becomes inactivated due to released heparin. The bio-responsive hydrogel quantitatively quenches blood coagulation over several hours in the presence of pro-coagulant stimuli and during repeated incubation with fresh, non-anticoagulated blood. These features enable the introduced material to provide sustainable, autoregulated anticoagulation, addressing a key challenge of many medical therapies. Beyond that, the explored concept may facilitate the development of materials that allow the effective and controlled application of drugs and biomolecules.

Designing hydrogels for controlled drug delivery

“…One example of the use of this is the incorporation of an MMP-cleavable peptide (GGRMSMPV) into a hyaluronic acid hydrogel that was used to deliver a recombinant tissue inhibitor of MMPs in a porcine model of myocardial infarction 113 . In addition to MMP-responsive hydrogels, there exist other cleavage systems that respond to biomolecules present in the body, such as glucose-responsive hydrogels for insulin delivery 114,115 and thrombin-responsive hydrogels to regulate blood coagulation 116,117 . Degradation can also be triggered in real time with externally provided cues.…”

“…Another example is sulfonate functional groups, which are used to increase electrostatic interactions between alginate and protein drugs to extend the release duration 159 . In recent approaches, the sulfation pattern of heparin has been tailored to further adjust the affinity of heparin to growth factors and thus control their release kinetics 116,160 .…”

Glycosaminoglycan‐Based Biohybrid Hydrogels: A Sweet and Smart Choice for Multifunctional Biomaterials

“…Hydrogels made of starPEG and HEP crosslinked by a thrombin-sensitive peptide linker were used to establish a thrombin-responsive, adaptive HEP release system. [173] In this system, if blood coagulation is activated, (A) thrombin is formed from prothrombin and initiates the self-amplifying blood coagulation cascade while simultaneously (B) cleaving the hydrogel, resulting in the release of HEP followed by (C) the HEP-catalyzed formation of the thrombin-antithrombin complex, which in turn inactivates thrombin and (D) terminates the degradation of the hydrogel (see Figure 17 ).…”

Thrombin‐Responsive Transcutaneous Patch for Auto‐Anticoagulant Regulation

“…Therefore, a controlled and on-demand drug delivery system, one that enhances therapeutic efficacy while minimizing side effects and time-to-treatment, is urgently needed for the management of thrombotic diseases. [10] …”