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Magnetically propelled microwheels for rapid thrombolysis in small arteries

Award Number: R01NS102465
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2018
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Magnetically propelled microwheels for rapid thrombolysis in small arteries - Project Summary: In small vessel stroke (SVS), which accounts for 20% of ischemic strokes, tissue plasminogen activator (tPA) is ineffective because it can take a prohibitively long time to diffuse to the clot, and catheter-based thrombectomy devices cannot access small vessels. Moreover, treatment associated hemorrhaging limits tPA use to within a few hours of the onset of symptoms for all ischemic strokes. As a result, there is an urgent need for strategies that overcome these limitations, particularly in SVS, while reducing the risks associated with tPA. Building on a successful previous work, a drug delivery strategy is proposed that can selectively target small artery occlusions and deliver mechanical force to accelerate thrombolysis. The objective of this proposal is to investigate and test within realistic models an approach where injected, dispersed magnetic beads are assembled into blood cell sized microwheels (µwheels) capable of targeting occlusive clots located in small vessels and lysing them with a combination of mechanical and biochemical action. The central hypothesis is that µwheels can (i) target occluded small arteries by exploiting the low flow regions at the entrance of these vessels, (ii) achieve reperfusion at rates an order-of-magnitude faster than soluble tPA, and (iii) improve outcomes in murine models of stroke. This hypothesis will be tested with the following specific aims: Aim 1. Identify magnetic field conditions for µwheels targeting of occlusions. µWheels will be assembled in flowing blood and directed to occluded channels or vessels. Microfluidic, zebrafish, and 3D human cerebrovascular models will be used to test the assembly and targeting. Aim 2. Determine rates for thrombolysis of occlusive thrombi using tPA functionalized µwheels. It is postulated that tPA functionalized µwheels can dissolve fibrin- and platelet-rich clots within microfluidic models and achieve reperfusion in zebrafish and 3D human cerebrovascular models, at rates significantly faster than soluble tPA. Aim 3. Measure the functional benefit of µwheel thrombolysis in vivo. In comparison to soluble tPA, µwheel mediated thrombolysis will improve safety, motor, and neurological outcomes in murine stroke models and can be visualized using high-resolution MRI and micro-CT. In Aims 1 and 2 the expected outcomes are identifying the operating conditions for µwheel assembly, targeting, and fibrinolysis that provide faster reperfusion compared to tPA and can be scaled-up to human-size vascular networks. In Aim 3, it will be shown that µwheel thrombolysis is a superior strategy to systemic administration of tPA in terms of neurobehavioral outcomes in a stroke model and can be imaged in vivo. This approach is significant because it could lead to the development of a more rapid and less invasive strategy for alleviating ischemia than methods currently available. This approach is innovative because of the use of external magnetic fields to propel fibrinolytic microdevices to the sites of occlusion and provide mechanical action to accelerate reperfusion time compared to systemic administration of tPA.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	TRUSTEES OF THE COLORADO SCHOOL OF MINES	1500 ILLINOIS ST	GOLDEN	CO	80401	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/1/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $493,791 )
2022	2022	TRUSTEES OF THE COLORADO SCHOOL OF MINES	1500 ILLINOIS ST	GOLDEN	CO	80401	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	3/31/2022	NON-COMPETING CONTINUATION	$493,791
														Subtotal = $493,791

Issue Date FY: 2021 ( Subtotal = $495,794 )
2021	2021	TRUSTEES OF THE COLORADO SCHOOL OF MINES	1500 ILLINOIS ST	GOLDEN	CO	80401	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	7/28/2021	NON-COMPETING CONTINUATION	$495,794
														Subtotal = $495,794

Issue Date FY: 2020 ( Subtotal = $497,738 )
2020	2020	TRUSTEES OF THE COLORADO SCHOOL OF MINES	1500 ILLINOIS ST	GOLDEN	CO	80401	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	3/30/2020	NON-COMPETING CONTINUATION	$497,738
														Subtotal = $497,738

Issue Date FY: 2019 ( Subtotal = $524,996 )
2019	2019	TRUSTEES OF THE COLORADO SCHOOL OF MINES	1500 ILLINOIS ST	GOLDEN	CO	80401	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/3/2019	NON-COMPETING CONTINUATION	$524,996
														Subtotal = $524,996

Issue Date FY: 2018 ( Subtotal = $567,336 )
2018	2018	TRUSTEES OF THE COLORADO SCHOOL OF MINES	1500 ILLINOIS ST	GOLDEN	CO	80401	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/20/2018	NEW	$567,336
														Subtotal = $567,336

Grand Total All Awards = $2,579,655

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Magnetically propelled microwheels for rapid thrombolysis in small arteries

Award Number: R01NS102465

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2018

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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