Researchers at the University of Ottawa used apple flesh to create ear-shaped human tissue and asparagus stems to regenerate the spinal cord

When Jessica Holmes, a chemistry major, joined the enhanced biology laboratory of biophysicist Andrew Palin at the University of Ottawa, she was tasked with an unusual task: to induce mammalian cells to multiply and grow in pasta. growing up healthily. In the name of regenerative medicine, Palin runs his laboratory like an experimental kitchen. There, researchers like Holmes are exploring common groceries to determine which contain microstructures that can shape newborn cells into functional tissues.

The flat petri dishes that scientists have been using since the 1800s cannot simulate the complex environment of the body, so Pelling Labs and others have been working hard to develop more realistic 3D "scaffolds" to support cell growth. However, Pelling's laboratory method is quite unconventional. They have determined that daily foods containing natural scaffolds can provide a physical basis for mammalian cells to divide, gather, communicate and assume specific roles with just a few adjustments.

As the Covid-19 pandemic escalated during Holmes' junior year, the university temporarily closed its research facilities to undergraduate students. Instead, Holmes' kitchen became her laboratory. After exhausting the list of potential porous noodles (from ramen to pea pasta) that could be good scaffolding, she abandoned her pasta project. Like many people during the spring lockdown, she started experimenting with bread recipes. In doing so, she made an amazing discovery: the porous structure of Irish soda bread provides an excellent support. Holmes and her colleagues in the Pelling laboratory sterilized the breadcrumbs, soaked them in nutrients, and then allowed the young cells to adhere to the breadcrumbs and penetrate the pores. In a study published in the journal Biomaterials in November, Holmes and her laboratory partners showed that this quick and simple formula contains only pantry ingredients and can grow mouse muscle, connective tissue and bone in a petri dish The precursor cells are as long as 4 weeks. Although this may seem like a strange job, through additional work, Holmes’ carbon-containing cell nursery may help researchers repair damaged tissues or regenerate organs.

Although other research groups have tried to use cell scaffolds made from wheat-derived proteins (such as gluten), the manufacture of these materials usually requires a lot of labor and resources. For example, an existing technology takes more than a week and requires specialized equipment to spin wheat protein into ultra-fine fibers to form a thin film on which cells can grow. As far as Pelling knows, his team is the first to use whole breadcrumbs to grow muscle and bone precursor cells.

Bread is just one of the many materials that can accomplish his mission, which is to formulate simple and inexpensive biological materials that support mammalian cells. In the 13 years since he started his laboratory, Palin has pushed mammalian cells to the limit by challenging the growth of mammalian cells in special environments. Pelling started with Lego bricks and has since turned to celery, apples, asparagus and other plant-derived scaffolds. (Bread contains wheat, so Pelling believes it is also plant-based.) "I have convinced myself that cells can grow on almost anything," he said.

The Pelling laboratory is at the forefront of a practice that dates back to 3000 BC, when the ancient Egyptians replaced their teeth with wood and repaired their skulls with coconut shells. Plants are great for this type of application because they contain cellulose, a carbohydrate built into their cell walls that provides strength and flexibility. Cellulose not only provides a structure for plant cells to grow, but also forms a porous network that can transport liquids and nutrients, just like a blood vessel network. Now, researchers realize that this material can provide similar benefits to mammalian cells.

Although modern efforts in regenerative medicine have used synthetic or bacterially produced cellulose, the Pelling laboratory sees no reason to reimagine the evolution of plants over millions of years. They use a common "decellularization" technique, including soap and water, to remove cells from fruits and vegetables. What is left is a natural vascularized cellulose scaffold, which can then be refilled with many types of cultured mammalian cells.

During lunch, Daniel Modulevsky, a former undergraduate researcher, presented the idea for the first plant decellularization research in the laboratory. The fleshy interior of the partially eaten apples of his colleagues may seem to provide a large, plastic structure to support mammalian cells. Online recipes indicated that Mackintosh apples are particularly rich, so Modulevsky began to peel, decellularize and wrap them with cells. After obtaining preliminary results, he realized his lunchtime hunch and stayed in Palin's laboratory to complete his PhD in biology. Since then, the researchers carved their decellularized apple flesh into ear-shaped human cell scaffolds. Recently, they even implanted apple scaffolds into living mice to cultivate connective tissue, collagen and blood vessel networks.

Although the unusual idea of ​​Pelling Lab was initially resisted by the scientific community, Modulevsky was pleased to see that their apple scaffold has provided seeds for many new research projects-from culturing bone-like tissue in rats When it comes to creating habitats for roundworms, these projects are popular research topics for biologists. "It's so cool to see how a small project can truly succeed in the world," he said.

At Boston College, biomedical engineer Glenn Gaudette is using similar decellularization techniques on spinach leaves, applying them to human heart cells to create cardiovascular tissue. He particularly likes spinach because its vein-like structure is very suitable for providing oxygen and nutrients to heart cells, as well as expelling metabolic waste. He plans to suture the central vein of decellularized spinach to the aorta, the main artery of the heart, to promote blood flow to the damaged heart muscle. The rest of the leaf will cover the entire area, expanding and contracting with each heartbeat. In the end, he also envisioned folding spinach leaves into the shape of a human heart and growing whole organs.

Gaudette predicts that it may take less than five years of long-term research before plant-based scaffolds can be used in clinical trials involving relatively simple tissues such as skin. Before that, some simple problems need to be solved, such as ensuring that the soap and detergent used for plant decellularization are completely washed away before implantation. More serious problems also exist. For example, researchers need to determine how the patient's immune system responds to cellulose (although Gaudette's unpublished work and Pelling's preliminary studies on mice and rats have shown promising results). Gaudette believes that a human strategy might involve restoring patients' own cells to stem cells and culturing them on spinach scaffolds before implantation. This may ultimately help the immune system accept the new tissue as part of the body.

According to Gaudette, there is still work to be done, but the researchers are getting closer. "Dreaming is fun, right?" he said. "I think we have the opportunity to create a new industry."

Like Pelling's laboratory, Gaudette's team has begun to design edible plant-based scaffolds that can produce environmentally friendly laboratory-grown meat. Although the breadcrumb holder is great for what Gaudette calls ground "mushy meat," the spinach holder may provide the rigid substrate needed for more structured cuts (such as steak).

As researchers continue to look for the next scaffold innovation in the aisles of the grocery store, it is clear that some plants are better suited for certain applications than others. For example, Gaudette's colleagues are using bamboo to regenerate teeth because of its toughness and small diameter. In contrast, peaches are too soft to support the structure used to grind and chew food.

Gaudette's work on spinach racks has become a recommended reading for students of the biomaterials course at the Bioengineer Grissel Trujillo de Santiago at the Monterey Institute of Technology in Mexico. In the laboratory led by her and her colleagues, Trujillo de Santiago is looking for a way to 3D print living tissue. Like Gaudette and Pelling, her goal is to devise elegant methods to create a vascular system that mimics human blood vessels. However, unlike Gaudette and Pelling, her team is using a water-filled network called hydrogel instead of cellulose.

She is interested in the possibility of using plant-derived structures to cultivate human tissues and eat meat. She said that especially the latter application requires scaffolding to be cost-effective and scalable to meet the needs of carnivores around the world.

In terms of medical use, Trujillo de Santiago said that the Pelling laboratory has successfully implanted apple stents into mice, which is very promising. She said that in addition to testing the scaffold in humans and ensuring that our immune system responds well to plant materials, researchers also need to prove that their implants will function like the tissues they intend to add or replace.

Although Trujillo de Santiago has not experimented with plant-derived scaffolds herself, she has already begun to use plant viruses to create structures for mammalian cells. These viruses are harmless to mammals such as mice and humans. They gather together to form a mesh material that helps fix cells. As she said: "We have this combination of biological materials in nature that can be used for human health."

Back at the University of Ottawa, Pelling, Modulevsky and their colleague Charles Cuerrier founded a company based on their most promising decellularized fruits and vegetables. One of their technology uses an asparagus scaffold to regenerate the spinal cord in rats, and was recently designated as a breakthrough device by the U.S. Food and Drug Administration. Unlike many existing scaffolds that are designed to degrade over time, the asparagus inserts in Pelling Labs are unlikely to be broken down by enzymes in the human body and release toxic byproducts. Although it will take several years before their decellularized asparagus can be tested in humans, the researchers are optimistic.

Not every vegetable can bring breakthrough equipment, but Pelling said that every new idea has value. "Your students—those who are willing to work in such laboratories—they are going through the discovery process," he said. "When you stumble upon a random discovery that is truly important, your entire team is trained and ready to execute."

After the strict pandemic restrictions were lifted, Holmes and her colleagues returned to campus. There, she continued to concoct various soda bread recipes and bake them in the laboratory's sterilization oven. She is about to graduate now and intends to apply the open-minded approach she learned in the Pelling laboratory to her career in speech pathology. Her main takeaway? "There are no bad ideas or ideas that are too much."

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