Enhanced Fibrinolysis with Magnetically Powered Colloidal Microwheels

Abstract

Thrombi that occlude blood vessels can be resolved with fibrinolytic agents that degrade fibrin, the polymer that forms between and around platelets to provide mechanical stability. Fibrinolysis rates however are often constrained by transport-limited delivery to and penetration of fibrinolytics into the thrombus. Here, these limitations are overcome with colloidal microwheel (µwheel) assemblies functionalized with the fibrinolytic tissue-type plasminogen activator (tPA) that assemble, rotate, translate, and eventually disassemble via applied magnetic fields. These microwheels lead to rapid fibrinolysis by delivering a high local concentration of tPA to induce surface lysis and, by taking advantage of corkscrew motion, mechanically penetrating into fibrin gels and platelet-rich thrombi to initiate bulk degradation. Fibrinolysis of plasma-derived fibrin gels by tPA-microwheels is fivefold faster than with 1 µg mL tPA. µWheels following corkscrew trajectories can also penetrate through 100 µm sized platelet-rich thrombi formed in a microfluidic model of hemostasis in ≈5 min. This unique combination of surface and bulk dissolution mechanisms with mechanical action yields a targeted fibrinolysis strategy that could be significantly faster than approaches relying on diffusion alone, making it well-suited for occlusions in small or penetrating vessels not accessible to catheter-based removal.

Engineered microparticles and nanoparticles for fibrinolysis

“…Magnetic fields overcome these limitations as they do not attenuate in tissue for frequencies < 30 Mhz . They can also be used to concentrate PA‐laden magnetic particles at the thrombus periphery . Magnetic nanoparticles (MNP) used for fibrinolysis are made from <30‐nm superparamagnetic iron oxide crystals of magnetite (Fe 3 O 4 ) or maghemite (γ‐Fe 2 O 3 ), FDA‐approved materials with low toxicity in humans, embedded in a polymer matrix .…”

“…A covalent bonding strategy is functionalization of PAA particle surfaces using N‐hydroxysuccinimide followed by coupling with tPA . Alternatively, streptavidin‐functionalized particles can be conjugated to biotinylated tPA . Such immobilization of PA protects the enzyme from inhibition by PAI‐1 and degradation in the liver.…”

“…Tasci et al. demonstrated enhanced fibrinolysis using a combination of biochemical and mechanical action using magnetically powered microwheels assembled in situ . Biotinylated tPA was immobilized on 1‐μm streptavidin‐coated MNP.…”

“…90 Alternatively, streptavidin-functionalized particles can be conjugated to biotinylated tPA. 74 Such immobilization of PA protects the enzyme from inhibition by PAI-1 and degradation in the liver.…”

“…96 Some of the most novel MNP strategies initiate thrombolysis through both chemical and mechanical mechanisms ( Table 2) cally powered microwheels assembled in situ. 74 Biotinylated tPA was immobilized on 1-μm streptavidin-coated MNP. The microwheels rolled to the interface of a plasma clot ( Figure 3D) and accumulated tPA at this interface at a concentration 50 times higher than the injected concentration.…”