Dose-Response Relationship and Threshold Drug Dosage Identification for a Novel Hybrid Mechanical-Thrombolytic System with an Ultra-Low Dose Patch.

INTRODUCTION: Ischemic stroke treatment has advanced in the last two decades and intravenous thrombolysis is now considered the standard of care for selected patients. Recanalization can also be achieved by mechanical endovascular treatment for patients with large vessel occlusions. Complicating treatment-related symptomatic intracerebral hemorrhage and prolonged needle-to-recanalization times have been identified as major determinants of poor three-month functional outcomes. A hybrid mechanical-thrombolytic system with a patch imbued with an ultra-low dose of thrombolytic agents loaded onto a stent-retriever has been developed. METHODS: In this study, the in situ dose-response relationship of the thrombolytic patch imbued with up to 1000 IU of urokinase plasminogen activator (uPA) was quantified using Raman spectroscopy. RESULTS: Thrombi of up to 400 µm thickness dissolved within 15 min when patches imbued with < 1% of the conventional thrombolysis therapy dosage were applied. The results demonstrated that low-dose thrombolytic patches can dissolve normal clots compressed in the blood vessel in a short time. 500 IU is the threshold uPA dosage in the thrombolytic patch that most effectively dissolves the clots. CONCLUSION: This study suggests that a novel endovascular stent-retriever loaded with an ultra-low drug dose fibrinolytic patch may be a suitable treatment for patients who are ineligible for conventional thrombolytic therapy.

Model development and comparison of low hemorrhage-risk endoluminal patch thrombolytic treatment for ischemic stroke.

Clot dissolution drugs delivered into the systemic circulation can dissolve intracranial blood clots in 90 min with 20-50% hemorrhage rate. Immobilizing <5% of the intravenous dosage on an endoluminal patch can reduce the dissolution time to <20 min with negligible hemorrhage risk. The thrombus dissolution behavior in endoluminal patch thrombolytic treatment is modeled and compared with experimental results from a companion study. Analyses showed that the thrombus dissolution time decreases with increasing dosage, but the dissolution time reaches a dosage-independent minimum when uPA dosage on the patch is >800 IU. Model analyses showed that dissolution time in the plateau regime is controlled by diffusion. Further results showed that dissolution time could be reduced in this regime by reducing thrombus thickness. This suggests that a stented endoluminal thrombolytic >800 IU patch that compresses the thrombus to thin the clot thickness can help reduce dissolution time. This ultra-low transition dosage (i.e., 800 IU), compared to 0.6-2.4 million IU in conventional thrombolysis suggests that hemorrhage risk in endoluminal patch thrombolytic treatment is low. The low hemorrhagic-risk endoluminal patch can be considered for use in patients who are ineligible for conventional thrombolytic treatment because of high hemorrhagic treatment risk.

Mechanical behavior of rf-treated thrombus in mechanical thrombectomy.

Intra-arterial mechanical thrombectomy (IAMT) treatments for ischemic stroke have higher recanalization rate, longer treatment time window and lower risk of symptomatic intracerebral hemorrhage (sICH). However, distal embolization may occur because of loose fragments produced during maceration and engagement. The naturally coagulated thrombus is fragile and has poor binding with thrombectomy device. Improvement of thrombus-device binding can reduce fragments breaking loose during wire pull and enhance protein crosslinking in the thrombus that can increase fragmentation resistance. The effects of in-situ applied radio frequency (rf) treatment on thrombus-wire binding and interfacial fracture have been examined in this study using wire pull tests that are mechanically analogous to the embolus retrieval method in thrombectomy. Wire inserted into a thrombus was pull tested after rf-treatment. Pull test results showed that rf-treatment improves binding and reduces thrombus slippage from over 90% to less than 10%. Fracture pull test results also showed that fracture energy density of thrombus-device interface increased 40X after rf-treatment. The dramatic increase in resistance against fracture suggests that the use of in-situ rf-treatment is a promising treatment addition to reduce distal embolization and improve clinical outcomes in mechanical thrombectomy.