Scientists have used 3D cell printing to create a model of skin that mimics the skin ailments associated with diabetes, allowing researchers to study symptoms and therapeutics related to these conditions without relying on animal models.

The study, published March 24 in Biomaterials, helps solve an important issue that arises when using synthetic tissue to study real illnesses: how to accurately replicate damaged or diseased tissue.

"The most important thing in tissue modeling is whether the symptoms that occur in actual patients can be practically represented in the engineered tissue model," said Dong-Woo Cho, a professor of mechanical engineering at Pohang University of Science and Technology, in South Korea. "This is because creating a model implementing the problem we are trying to solve is the first step in solving the problem."

Diabetes affects 34.2 million Americans, or just over one in 10. One of the many challenges patients with diabetes face is that their skin is more prone to infection and irritation.

Poor circulation in diabetes patients leads to poor healing time for skin injuries, as well as the death of skin tissue. Cho and his team focused on diabetic foot ulcers, which occur when skin on the foot breaks down, exposing layers underneath.

"Although early prevention and treatment prior to development [of the] ulcer is known as the best way of treatment, it is easy to miss the appropriate treatment time because many patients become less sensitive to feel pain, and the wounds mostly occur in the foot, where it is difficult to recognize," Cho said.  

Human skin has two layers: the lower dermis and the upper epidermis. The epidermis is then further composed of several layers that come about when keratinocytes, a type of epidermal cell, differentiate into various forms.

Mimicking this complicated series of layers is the major challenge of skin-tissue engineering. Previous studies have successfully used 3D-printed cells to mimic human skin, but their focus was the creation of a healthy equivalent for skin. Creating a synthetic skin that can also demonstrate the pathology of specific illnesses is a different matter entirely.

To tackle this challenge, the team used 3D bioprinting to produce the initial layers of skin cells. However, to make the model mimic diabetic skin, the researchers then relied on the interaction between two different types of cells to stimulate the model to produce diabetic skin cells.

The researchers used nondiabetic epidermal cells, like other printed skin models. However, they incorporated fibroblasts — cells that produce collagen — cultured from diabetic skin.

"We hypothesized that, through this interaction, keratinocytes would become diabetic under the influence of diabetic fibroblasts in the process of differentiation," Cho said.

When they tested their skin model, they found that it exhibited a tendency to heal slowly, just as real diabetic skin does. They also successfully incorporated additional artificial layers for fat and blood vessels to prove that their model could be used to test new drugs.

"The reason why we added the fat and blood vessels is because drugs are generally delivered to the skin through bloodstream within the fat layer," Cho said. "Drugs known to alleviate diabetes were flowed into the engineered blood vessel of the skin model to see if the drugs had the similar effects on the developed model as seen in real patients."

In addition to successfully modeling the effects of diabetes drugs, the skin also showed additional properties associated with diabetic skin, such as that tendency to heal slowly. When the researchers induced hyperglycemia, or high blood sugar, the skin model also showed insulin resistance and dysfunction of the fat and vascular tissue.

The result of the researchers' labor is not only a successful model of diabetic skin but also a promising new method of 3D bioprinting that can be applied to other diseases.

"We believe that our new 3D bioprinting platform for developing diseased skin [models] can be applied to pathological and pharmacological studies, as well as a promising alternative to the current platform mainly focused on animal models," Cho said.

The team is now creating new models to account for environmental factors, such as diet and exercise, that contribute to diabetes. And while their work focuses mainly on one disease, the researchers are optimistic that modeling diseased tissues to evaluate therapeutics will prove an important technique across medicine.

"Due to the COVID-19 pandemic, the world has watched the need for a fast and reliable screening platform for new drugs," Cho said. "We hope that our research for engineering various artificial tissues in progress will make a big contribution to humanity and society in the near future."

The study, "Engineering of diseased human skin equivalent using 3D cell printing for representing pathophysiological hallmarks of type 2 diabetes in vitro," published March 24 in Biomaterials, was authored by Byoung Soo Kim, Pusan National University; and Minjun Ahn, Won-Woo Cho, Ge Gao, Jinah Jang and Dong-Woo Cho, Pohang University of Science and Technology.