Stroke, the main cause of adult disability, leaves a hole, or cavity, in the brain, destroying tissue and cell networks. Physical therapy is the only approved treatment for stroke, relying on the brain’s ability to rewire itself to regain function without healing the damaged tissue. This highlights an opportunity for regenerative medicine to improve healing and long term outcomes for stroke patients.
A possible solution to stroke therapy shortcomings
Transplanting neural stem cells into the damaged tissue has not yet been able to replace tissue, and a brain cavity remains in stroke survivors. An alternative and cell-free approach to stroke therapy may be injection of an extracellular matrix (ECM) scaffold into the brain cavity. This scaffold can fill the cavity and support migration into the damaged area of therapeutic cells already in the brain.
Harmanvir Ghuman, et al., at the University of Pittsburgh, made the initial steps to create this type of scaffold, allowing cells from the brain to migrate into the cavity left by a stroke.
“The use of an acellular extracellular matrix (ECM), formulated to produce a hydrogel in situ within the cavity formed by a stroke, was investigated as a method to replace necrotic debris and promote the infiltration of host brain cells.” – Harmanvir Ghuman, et al.1
The experiment to demonstrate a viable stroke therapy scaffold
Extracellular matrix from bladder tissue promotes growth of neurites. Tissue from an adult pig bladder was used to create the decellularized ECM scaffold for this experiment. The bladder tissue was washed with a decellularization solution,2 lyophilized,3 physically pulverized, then chewed up into even smaller pieces using enzymes. The result was a water soluble powder that was injectable with a needle, but when heated to body temperature would become a gel.
The researchers used rats as the stroke model. They induced a stroke, leaving cavities that ranged from 40 mm3 to 290 mm3. Fourteen days later, the acellular ECM scaffold was injected, filling the brain cavity. After stroke, the cavities are not truly empty, as they still have dead tissue debris and fluid inside. Therefore, two holes are needed for this treatment: one hole to inject the scaffold, and a second hole so the original contents can drain. Without the drain, injecting anything would cause too much pressure in the skull, creating a second brain injury.
One day after the scaffold was injected, the researchers ended the experiment and studied the brains. Even in a short, 24-hour time period, significant cell numbers infiltrated the ECM scaffolds. All resident brain cell types were identified inside the scaffolds, though a majority were macrophages responsible for clearing dead tissue and foreign material.
Close contact between the scaffold and brain tissue was an important factor in the ability of cells to migrate into the scaffold. Cells penetrated deeper into the scaffold when the scaffold was in direct contact with brain tissue, with a wide variety of brain cells following the initial trail. This means injecting the correct volume of ECM, completely filling the cavity, is important to the success of this treatment.
Results show promise for a new stroke therapy
Remodeling, or degradation, of the ECM scaffold by macrophages releases chemical signals from the ECM that benefits tissue regeneration, attracting cells that can build new tissue. The researchers think that the destruction of the scaffold by the macrophages is actually constructive. They have a “pioneering function,” creating tunnels filled with therapeutic proteins that brain cells were seen to follow.
The results indicate that an extracellular matrix scaffold has the potential to regenerate tissue in the brain cavity left by a stroke. This would be a level of healing that is not possible with current stroke therapy, and suggesting the possibility of a better quality of life following a stroke.
However, the utility of replacing the damaged brain tissue is only assumed at this point. Weeks to months would pass before functional brain tissue would fill the stroke cavity, meaning the brain will have a long wait. During that time the brain will likely rewire itself anyway, providing its own solution to the lost function, just as it does with current therapies. It remains to be seen whether the long term outcome for a stroke patient would improve just because the hole is filled with new tissue.
It is, of course, worth trying.
- Harmanvir Ghuman, Andre R. Massensini, Julia Donelly, Sung-Min Kim, Christopher J. Medberry, Stephen F. Badylak, Michel Modo. “ECM hydrogel for the treatment of stroke: Characterization of the host cell infiltrate.” Biomaterials 91 (2016) 166-181.
- All original cells need to be removed to prevent an immune response, leaving only structural components and proteins.
- Lyophilization removes all volatile liquids, leaving a completely dry and porous sponge.