Continuing with the theme of interesting biomaterials-related talks at the recent Till & McCulloch Meetings in Toronto, Canada, was the one delivered by Professor Molly Shoichet from the University of Toronto. Her group focuses on designing polymer scaffolds to deliver drugs and cells as part of regenerative medicine strategies for the repair and restoration of injured central nervous systems (CNS) and eyes.
Delivering drugs and stem cells into the CNS has two main limitations. First, there is the cerebrospinal fluid (CSF), which protects the brain and spinal cord from injury, but at the same time displaces anything injected into it. Second, there are two permeability barriers: the blood brain barrier (BBB) and the blood spinal cord barrier (BSCB). These protective membranes will not allow bacteria and most cells and drugs to pass through to the brain or spinal cord. Thus, it is really challenging to simply inject drugs or cells into the blood stream or the CSF and keep them at the target site long enough to promote functional recovery.
The Shoichet group has come up with solutions to this challenge and Dr. Shoichet’s talk centered on HAMC and how it can be used in cell treatment strategies in models for stroke and blindness. HAMC is a 3D construct of hyaloronan-based hydrogel with methylcellulose added to it. It has shear thinning and forms a gel at 18 degrees – meaning it easily passes through a really thin needle (as small as 34 gage) and forms a 3D construct when injected inside the body. This is very useful since transplanting cells into a site in the CNS will not cause any damage to the tissue.
HAMC paves the way for local cell and drug delivery and keeps them at the site of injection. The Shoichet team used this gel to transplant cells into injury models of stroke and blindness in animals.
In collaboration with the Morshead team, at the University of Toronto, Dr. Shoichet’s group transplanted neural stem cells (NSC) isolated from stroke-injured mice brains, and suspended in HAMC, directly on top of the stroke site. Interestingly, they observed higher cell survival when the hydrogel/cell construct was added directly to the stroke site. Also, mice that received cells in HAMC achieved some functional recovery and the NSCs were able to differentiate into neural cells called astrocytes. Among other functions, these cells provide metabolic and structural support to the other types of neural cells in the CNS.
Stem cells have long been studied for their potential in restoring vision for those affected by diseases such as age-related macular degeneration or retinitis pigmentosa. In both of these, the light-sensing cells in the eye’s retina, called the photoreceptors, are lost. Similar to the brain, the main limiting factor is delivering stem cells into the correct space at the back of the eye and keeping them there.
Shoichet’s team collaborated with the Van der Kooy team, at the University of Toronto, and developed light-sensitive stem cells and transplanted them with HAMC into the mice’s eyes. The cells inside HAMC survived longer, which was shown to be a direct effect of the hyaloronan in the construct. Additionally, the group added a drug to enhance stem cell integration into the host tissue, called alpha-aminoadipic acid, three days before cell-HAMC transplantation.
This combinatorial strategy of cells, biomaterials and drugs resulted in improved survival of the stem cells, better integration into the host tissue and some restoration in function. When the blind mice were exposed to intense light, the pupils got smaller, which indicates light sensitivity. This pupillary response was 85 to 90 percent of what is seen in a normal mouse. This study was published in the journal Stem Cell Reports.
These results are a huge step forward in this field, but much further research is needed. To restore complete function to the injured brain and eye, researchers will need to identify the mechanisms involved in stem cell survival and integration, the ideal combination of cells and the correct supplements to be used.
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