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Visish M. Srinivasan, Stephen R. Chen, Kevin M. Camstra, Gouthami Chintalapani and Peter Kan

OBJECTIVE

Stroke is a major cause of disability and death in adults. Several large randomized clinical trials have shown the significant benefit of mechanical thrombectomy with modern stent retrievers in the treatment of large-vessel occlusions. However, large clots located at bifurcations remain challenging to treat. An in vivo model of these recalcitrant clots needs to be developed to test future generations of devices.

METHODS

Autologous blood was drawn from anesthetized swine via a femoral sheath. Blood was then mixed with thrombin, calcium chloride, and saline, and injected into silicone tubing to form cylindrical clots in the standard fashion. Matured clots were then delivered in an unfragmented fashion directly into the distal extracranial vasculature, at branch points where vessel sizes mimic the human middle cerebral artery, by using Penumbra aspiration tubing and the Penumbra ACE68 reperfusion catheter.

RESULTS

A total of 5 adult swine were used to develop the model. The techniques evolved during experiments in the first 3 animals, and the last 2 were used to establish the final model. In these 2 swine, a total of 8 autologous clots, 15–20 mm, were injected directly into 8 distal extracranial vessels at branch points to mimic a bifurcation occlusion in a human. All clots were delivered directly at a distal bifurcation or trifurcation in an unfragmented fashion to cause an occlusion. Ten revascularization attempts were made, and none of the branch-point occlusions were fully revascularized on the first attempt.

CONCLUSIONS

Using novel large-bore distal access catheters, large unfragmented clots can be delivered into distal extracranial vessels in a swine occlusion model. The model mimics the clinical situation of a recalcitrant bifurcation occlusion and will be valuable in the study of next-generation stroke devices and in training settings.

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Visish M. Srinivasan, Joy Gumin, Kevin M. Camstra, Stephen R. Chen, Jeremiah N. Johnson, Yuzaburo Shimizu, Brittany C. Parker Kerrigan, Elizabeth J. Shpall, Frederick F. Lang and Peter Kan

OBJECTIVE

Bone marrow–derived human mesenchymal stem cells (BM-hMSCs) have been used in clinical trials for the treatment of several neurological disorders. MSCs have been explored as a delivery modality for targeted viral therapeutic agents in the treatment of intracranial pathologies. Delta-24-RGD, a tumor-selective oncolytic adenovirus designed to target malignant glioma cells, has been shown to be effective in animal models and in a recent clinical trial. However, the most efficient strategy for delivering oncolytic therapies remains unclear. BM-hMSCs have been shown to home toward glioma xenografts after intracarotid delivery. The feasibility of selective intraarterial infusion of BM-hMSCs loaded with Delta-24-RGD (BM-hMSC-Delta-24) to deliver the virus to the tumor is being investigated. To evaluate the feasibility of endovascular intraarterial delivery, the authors tested in vitro the compatibility of BM-hMSC-Delta-24 with a variety of commercially available, clinically common microcatheters.

METHODS

BM-hMSCs were cultured, transfected with Delta-24-RGD, and resuspended in 1% human serum albumin. The solution was then injected via 4 common neuroendovascular microcatheters of different inner diameters (Marathon, Echelon-14, Marksman, and SL-10). Cell count and viability after injection through the microcatheters were assessed, including tests of injection velocity and catheter configuration. Transwell assays were performed with the injected cells to test the efficacy of BM-hMSC-Delta-24 activity against U87 glioma cells. BM-hMSC-Delta-24 compatibility was also tested with common neuroendovascular medications: Omnipaque, verapamil, and heparin.

RESULTS

The preinfusion BM-hMSC-Delta-24 cell count was 1.2 × 105 cells/ml, with 98.7% viability. There was no significant difference in postinfusion cell count or viability for any of the catheters. Increasing the injection velocity from 1.0 ml/min to 73.2 ml/min, or modifying the catheter shape from straight to tortuous, did not significantly reduce cell count or viability. Cell count and viability remained stable for up to 5 hours when the cell solution was stored on ice. Mixing BM-hMSC-Delta-24 with clinical concentrations of Omnipaque, verapamil, and heparin prior to infusion did not alter cell count or viability. Transwell experiments demonstrated that the antiglioma activity of BM-hMSC-Delta-24 was maintained after infusion.

CONCLUSIONS

BM-hMSC-Delta-24 is compatible with a wide variety of microcatheters and medications commonly used in neuroendovascular therapy. Stem cell viability and viral agent activity do not appear to be affected by catheter configuration or injection velocity. Commercially available microcatheters can be used to deliver stem cell neurotherapeutics via intraarterial routes.