Accelerated thrombolysis by intra-arterial low dosage thrombolytic patch

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 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.

Date of Award	2017
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology