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Protein-Eluding Scaffolds Help Grow New Blood Vessels

Antigen-releasing scaffold

Scanning electron microscope image of an antigen-releasing scaffold that recruits antigen-specific T-cells to sites of peripheral artery disease injuries. (Wyss Institute, Harvard University)

31 July 2019. A polymer frame infused with proteins that stimulate immune cells encourages growth of new blood vessels in lab mice with peripheral artery disease. Researchers from the Wyss Institute for Biologically Inspired Engineering at Harvard University describe their discovery in today’s issue of the journal Science Advances.

A team from the tissue engineering lab of David Mooney at Wyss Institute and Harvard’s engineering school is seeking better treatment options for people with peripheral artery disease, a form of ischemia or narrowing and blocking of arteries usually in the legs or feet. The arteries narrow because of waxy plaque build-ups similar to atherosclerosis in the heart causing pain and numbness.  Treating peripheral artery disease includes medications like those for high blood pressure and cholesterol, as well as lifestyle changes: smoking cessation, more exercise, and a healthier diet.

Mooney and colleagues propose a more direct treatment for severe cases of peripheral artery disease, growing more blood vessels in limbs to replace the blood flow in blocked arteries. Up to now, proteins that grow blood vessels do not last long nor are they retained in the body, Thus the treatment would need to deliver these blood-vessel growth proteins over a sustained period of time.

Their solution starts with a frame or scaffold made of polylactide-co-glycolide, or PLG, a biocompatible and biodegradable polymer approved by FDA for drug delivery and medical devices. This scaffold is infused with antigen proteins that stimulate a response from T helper 2 T-cells in the immune system, which secrete other proteins stimulating blood vessel growth. In addition, this type of T-cell also has a memory function, so once activated, the cells remain able to respond to stimulating signals. This memory feature is important, since nearly all children in the U.S. are vaccinated against diphtheria, tetanus, and whooping cough containing aluminum, an adjuvant, or supplementary immune-system simulator particularly effective with T helper 2 T-cells.

To test the scaffold, the researchers induced lab mice with peripheral artery disease in their hind limbs, and vaccinated the test mice with aluminum as a stand-in for childhood vaccines. The team also vaccinated the mice with the model antigen protein ovalbumin that interacts with aluminum in the immune system. The mice then received implants of PLG scaffolds infused with ovalbumin in their hind limbs to trigger T helper 2 T-cells for stimulating blood vessel growth.

The results show mice receiving the initial aluminum and ovalbumin vaccinations, as well as the ovalbumin-infused scaffolds have more blood vessel growth, less tissue damage, and better blood perfusion than similar mice either not vaccinated or not receiving an implanted scaffold. Mice receiving both vaccinations and scaffolds also show more leg muscle regeneration than similar mice not receiving the full treatments.

Former doctoral student and first author Brian Kwee says in a Wyss Institute statement that the team’s discovery, “provides a new method of enhancing blood vessel formation that does not rely on traditional biologics, such as cells, growth factors, and cytokines, that are typically used to promote vascularization.” Kwee, now a postdoctoral researcher at the Food and Drug Administration adds that the treatment, “more broadly suggests that advances in bioengineered T-cell therapies, which have traditionally been used to treat cancers, may be utilized to promote wound healing and regeneration.”

The authors plan to file for a patent on the technology.

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