THESIS
2017
xiv, 132 pages : illustrations ; 30 cm
Abstract
Ischemic stroke is caused by a thrombus blocking a blood vessel in the brain. The blocked
vessel can be recanalized by intravenous injection of 0.6 – 2.4 million International Units of
urokinase plasminogen activator (uPA) for 90 minutes. The dissolution time can be reduced
by increasing thrombolytic agent dosage, but the high dosage in the blood vessel can induce
side effects including symptomatic intracranial hemorrhage (SICH) and death. The risk of side
effects excludes a large portion of patients from receiving thrombolysis treatment. Localizing
the thrombolytic agents can increase the effective concentration at the thrombus site without
increasing the risk of side effects at other locations in human body, but few methods can provide
local dosing at the thrombus while restri...[
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Ischemic stroke is caused by a thrombus blocking a blood vessel in the brain. The blocked
vessel can be recanalized by intravenous injection of 0.6 – 2.4 million International Units of
urokinase plasminogen activator (uPA) for >90 minutes. The dissolution time can be reduced
by increasing thrombolytic agent dosage, but the high dosage in the blood vessel can induce
side effects including symptomatic intracranial hemorrhage (SICH) and death. The risk of side
effects excludes a large portion of patients from receiving thrombolysis treatment. Localizing
the thrombolytic agents can increase the effective concentration at the thrombus site without
increasing the risk of side effects at other locations in human body, but few methods can provide
local dosing at the thrombus while restricting the dispersion. An intra-arterial thrombolytic
patch loaded is developed to fill this gap. The thrombolytic drug is delivered locally at the
thrombus to accelerate the dissolution process while limiting drug dispersion away from the
patch. Tests showed that patches loaded with <5% of dosage used in intravenous treatment
reduced the dissolution time is to <20 minutes. However, further tests showed that the reduction
of dissolution time does not increase linearly with dosage, but is asymptotically bounded,
suggesting diffusion-limited dissolution at large dosage. The clot dissolution behavior in patch
treatment is modeled using a reaction kinetics model. The model showed that the dissolution is
diffusion-limited with a threshold drug dosage at 500 IU of uPA, beyond which the thrombus
dissolution process is limited by the diffusion rate. Model showed that treatment time can be
reduced by reducing thrombus thickness. The relative dominance of the dosage-limited and
diffusion-limited regimes with treatment parameters are examined by characterizing the change
of fibrin concentration inside the thrombus using Raman spectroscopy. The results confirmed
the presence of the two regimes, and the experimental results compared well with model results.
A prototype of the thrombolytic patch is tested in both in vitro and in vivo experiment.
Experimental results showed that thrombus-blocked vessels can be effectively recanalized by
the device and the thrombi can be dissolved under 20 minutes while minimizing the risk of
hemorrhage. With successful in vitro demonstration, in vivo animal tests maybe conduct to ready the device for clinical trials. If successful, the thrombolytic patch treatment may be used in patients who are excluded from conventional thrombolysis because of hemorrhage risk.
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