Abstract
Fibrinolytic drugs such as recombinant tissue plasminogen activator (tPA) have been successfully used to reestablish blood flow in thrombotic strokes. However, they can also lead to intracranial hemorrhaging, must be used within hours of the onset of symptoms, and have limited efficacy in small vessel occlusions distal to major cerebral arteries. Alternatively, catheter-based thrombectomy devices can restore blood flow quickly but are invasive, limited to larger arteries, and can leave residual prothrombotic material on vessel walls. An approach that overcomes these limitations is the injection of individual superparamagnetic particles coated with fibrinolytic drugs that, upon application of a rotating magnetic field, self-assemble into microbots we call microwheels capable of translating to and directly attacking thrombi. We describe an approach that uses the vessel wall to propel in situ assembled microwheels via rolling.1 Driven by low-strength external magnetic fields (~10 mT), microwheel movement occurs with greatly improved speeds (>100 µm/sec) and directional control compared to approaches that use magnetic field gradients to direct similar types of microdevices. Using this approach, tPA-functionalized particles are introduced at a subtherapeutic concentration, which accumulate to therapeutic levels at the periphery of a thrombus. Fibrinolytic microwheels bore into fibrin-rich and platelet-rich thrombi by mechanical action and accomplish reperfusion faster than soluble tPA at comparable concentrations.2 For example, fibrinolysis of plasma-derived fibrin gels is five-fold faster using tPA-microwheels compared to 1 µg/mL tPA. Using a microfluidic model of vascular injury, ~100 µm sized platelet-rich thrombi were formed on collagen-tissue factor surfaces and then ablated with tPA-microwheels in less than five minutes. Combining mechanical and biochemical methods, this approach could reduce the risk of bleeding associated with fibrinolytics and broaden their indications.
1. Tasci TO, Herson PS, Neeves KB, Marr DWM. Surface-enabled propulsion and control of colloidal microwheels. Nature Communication, 2016;7:10225.
2. Tasci TO, Disharoon D, Schoeman RM, Rana K, Herson PS, Marr DWM, Neeves KB. Enhanced fibrinolysis with magnetically powered colloidal microwheels. Small;in press
Disclosures
Neeves: Colorado School of Mines: Patents & Royalties.
Magnetically Powered Microbots: A Novel Approach to Thrombolysis?