Improving the Efficiency of Neural Stem Cell Delivery to the Area of Stroke

drs m and b

Work that was funded through the National Institute of Biomedical Imaging and Bioengineering as part of the Quantum Program and conducted by McGowan Institute for Regenerative Medicine affiliated faculty member Michel Modo, PhD, Professor in the Departments of Radiology and Bioengineering at the University of Pittsburgh, and colleagues, recently was published in the journal Brain Research Bulletin. Dr. Modo is the corresponding author on the study and McGowan Institute deputy director Stephen Badylak, DVM, PhD, MD, Professor in the Department of Surgery at Pitt and Director of the Center for Pre-Clinical Tissue Engineering within the Institute, is a co-author.

In the paper, the researchers report the implantation of “tissue constructs” consisting of neural stem cells and endothelial cells encapsulated in polyethylene glycol microspheres, suspended in extracellular matrix hydrogel into stroke cavities. This dramatically improved the efficiency of neural stem cell delivery to the area of stroke compared to cell suspensions. Conceptually this is a major step forward to potentially build off-the-shelf tissue constructs for the rapid reconstruction of brain tissue, potentially even allow pre-differentiation of these constructs prior to delivery. The manuscript is focused on technical feasibility.

The abstract follows:

Intracerebral implantation of neural stem cells (NSCs) to treat stroke remains an inefficient process with <5% of injected cells being retained. To improve the retention and distribution of NSCs after a stroke, we investigated the utility of NSCs’ encapsulation in polyethylene glycol (PEG) microspheres. We first characterized the impact of the physical properties of different syringes and needles, as well as ejection speed, upon delivery of microspheres to the stroke injured rat brain. A 20 G needle size at a 10 µL/min flow rate achieved the most efficient microsphere ejection. Secondly, we optimized the delivery vehicles for in vivo implantation of PEG microspheres. The suspension of microspheres in extracellular matrix (ECM) hydrogel showed superior retention and distribution in a cortical stroke caused by photothrombosis, as well as in a striatal and cortical cavity ensuing middle cerebral artery occlusion (MCAo). Thirdly, NSCs or NSCs + endothelial cells (ECs) encapsulated into biodegradable microspheres were implanted into a large stroke cavity. Cells in microspheres exhibited a high viability, survived freezing and transport. Implantation of 110 cells/microsphere suspended in ECM hydrogel produced a highly efficient delivery that resulted in the widespread distribution of NSCs in the tissue cavity and damaged peri-infarct tissues. Co-delivery of ECs enhanced the in vivo survival and distribution of ∼1.1 million NSCs. The delivery of NSCs and ECs can be dramatically improved using microsphere encapsulation combined with suspension in ECM hydrogel. These biomaterial innovations are essential to advance clinical efforts to improve the treatment of stroke using intracerebral cell therapy.