BioTechniques News
Beatrice Bowlby
Original story from Duke University (NC, USA).
Delivered more than 24 hours after a stroke in mice, an injectable biomaterial harnesses the immune system to promote vascular repair, neural remodeling and improved motor performance.
Biomedical engineers at Duke University (NC, USA) have developed an injectable biomaterial that helps transform the cavity left behind after a stroke caused by a blood clot into an environment more supportive of repair. By recruiting the body’s own immune cells, the treatment promoted the growth of new blood vessels, supported neural remodeling and improved motor performance in mice.
Every year, millions of people experience strokes caused by blood clots, called ischemic strokes. Immediate treatments, including clot-dissolving drugs and mechanical removal of the clot, can restore blood flow and preserve threatened brain tissue. But these treatments cannot replace tissue that has already been lost.
Large strokes can result in substantial tissue loss and leave behind a cavity at the site of the injury. After the clot is removed, recovery relies largely on rehabilitation, which helps surviving brain circuits adapt but does not directly repair the damaged area.
“Once brain tissue has been lost, restoring blood flow is no longer enough,” commented Tatiana Segura, the Robert Plonsey Distinguished Professor of Biomedical Engineering at Duke. “Our goal is to engineer the injured space so that immune, vascular and neural repair processes can begin to work together.”
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Segura and her team set out to create those conditions by using MAPS, or microporous annealed particle scaffolds, which are individual hydrogel microparticles that form a porous microstructure for cells to build on to regrow neural tissue. Building on their earlier successes with the innovative biomaterial, they looked to harness the abilities of the body’s immune system to guide and improve repairs.
To pull in helpful immune cells, the team turned to astrocytes, star-shaped cells that support normal brain function and respond rapidly to injury. Astrocytes communicate with other cells in part by releasing extracellular vesicles (EVs), which are nanoscale packages that carry proteins, lipids and genetic material.
The researchers collected EVs from lab-grown astrocytes and experimented with adding various signaling molecules to attract immune cells and promote vascular repair and functional improvement. Rather than simply injecting the EVs, the team used a chemical reaction to anchor them to the surfaces of the hydrogel microparticles. This kept the signals localized within the scaffold, where incoming cells could encounter them.
“We are not simply placing a material into the brain,” Segura explained. “We are engineering a local environment that can coordinate several parts of the repair response.”
One combination of signaling molecules, IL-4 and C1q, proved best at attracting helpful immune cells into the damaged region, including macrophages and an unexpectedly persistent population of neutrophils. Neutrophils are commonly associated with inflammation and tissue damage during the early stages of stroke. But the study suggests that, at a later stage and within the right material environment, these cells can also contribute to repair.
When the researchers depleted the neutrophil-rich immune-cell population, blood vessel growth and scaffold remodeling were markedly reduced. This finding showed that the cells were important contributors to the repair response.
“This result changes how we think about neutrophils after stroke,” shared Shangjing Xin, lead scientists of the study and a postdoctoral fellow in the Segura laboratory. “Their role appears to depend on when they arrive, where they are located and the signals they receive from their surroundings. Our study demonstrates a potential engineering strategy to recruit and retain these cells at the right time.”
The immune response was accompanied by the formation of blood vessels throughout the treated cavity. The researchers also observed increased axonal fibers, which are key structures in brain cells, within and around the damaged region.
Mice receiving the optimized scaffold also performed better on a grid-walking test that measures errors in forelimb placement. By eight weeks, their performance was statistically indistinguishable from that of healthy control mice, and the improvement was sustained throughout the study.
Importantly, EVs delivered without the MAP scaffold did not produce comparable vascular repair. This result showed that the biomaterial was not simply carrying a therapeutic cargo. Its porous structure and ability to localize the EV signals were essential to the response.
While these findings are a step in the right direction, the findings remain preclinical. The evolving treatment was tested in mouse models by directly injecting it into the damaged site. Additional studies will be required to evaluate its safety, determine how the different immune-cell populations contribute to recovery, and test the approach in larger and more clinically representative stroke models.
The current study used EVs collected from primary rat astrocytes. As a next step, the Segura laboratory is exploring EVs produced by human induced pluripotent stem cell-derived astrocytes. This approach could provide a more scalable and clinically relevant source of EVs while allowing the researchers to better control the signals they carry.
“You do not restore an ecosystem simply by containing the initial damage,” Segura concluded. “You have to create the conditions that allow life to return. That is how we think about the stroke cavity. The material is not intended to reproduce the brain itself, but to create an environment where the body’s own cells can enter, communicate and participate in rebuilding vascularized tissue.”
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