Cell Therapy, Devices, and Diabetes: Richard Youngblood

Richard Youngblood

According to the American Diabetes Association, over a million Americans have type 1 diabetes, and many of us know friends and family members with this disease. While the more prevalent type 2 diabetes is defined by insulin resistance, type 1 diabetes is an autoimmune disease where the body’s immune cells target and kill its own insulin-producing cells in the pancreas, the beta cells. Without these cells, the body fails to produce insulin in response to glucose, which can lead to a variety of long-term consequences, including heart issues and vision loss. Currently, type 1 diabetes is managed by lifestyle changes and insulin therapy. There is no cure.

But there are communities of researchers working on new technologies and approaches to treat and manage this disease. Richard Youngblood is a biomedical engineering grad student working toward his PhD in the lab of Lonnie Shea at the University of Michigan. Richard and his colleagues are working to replicate pancreatic tissue in a bioengineered scaffold that could one day be implanted into patients to provide an alternative source of insulin.

To create this artificial pancreas, Richard and the lab are taking a cell therapy approach and converting human pluripotent stem cells into pancreatic islet cells, which include the insulin producing beta cells.

Growing cells to produce insulin when exposed to glucose is one challenge, but another hurdle is developing the delivery mechanism of these cells into the patient. Previously, some researchers have tried using biocompatible pouches. These pouches would contain the insulin producing cells and would be implanted into patients. Some progress was made with these devices, as were tested in clinical trials and were deemed safe. However, it was found that the pouches lost their efficacy over time. Because the pouches weren’t permeable, the cells contained within were unable to receive a constant supply of oxygen and other nutrients, limiting their effectiveness. Additionally, it was found that a fibrous encapsulation developed around the pouches over time, essentially sealing them off from the rest of the body and rendering them ineffective.

Richard and the other members of the Shea lab have identified a possible solution to these problems. Instead of growing cells in a pouch, they grow cells in a scaffold made of a porous material. The pores allow the contents of the device to better interact with the host body, allowing for blood vessel formation and other natural processes to take place. This ensures that the cells in the device get oxygen and other nutrients and hopefully leads to better integration with the body. Conceptually, these differences will better mirror normal functioning tissue in the body and avoid the pitfalls of the earlier pouches, including the activation of the encapsulation response.

The device itself looks like a small plastic disk. To make it, Richard takes polymer microparticles and mixes them with salt. This mixture is then pressed into a disk using a hydraulic press, and vacuum pressure fuses the polymer particles together. The end result of this process is a solid disk of plastic and salt crystals. To form the micropores, the disk is placed in water, which dissolves the salt to leave voids and channels. After this step, the disk looks like a small sponge or a highly perforated piece of Swiss cheese under a microscope.

The disk is seeded with pancreatic progenitor cells differentiated from pluripotent stem cells, which are defined by their ability to self-renew and differentiate into various cell types. Once loaded with cells, the device is exposed to various growth factors that shepherd the cells toward pancreatic cell characteristics.

Remarkably, Richard has found that in this environment, these cells fill the pores of the device and differentiate into various cells found in the pancreatic islet, resembling mini pancreases. Importantly, these cells appear to be glucose-responsive, meaning that they produce insulin when exposed to glucose. This means that, theoretically, in a type 1 diabetes patient who is lacking insulin producing cells, this device could act as an alternative source of insulin in response to blood sugar levels.

To test the feasibility of this idea outside of a petri dish, Richard is working to implant the device into mice that lack beta cells. Like human diabetes patients, these mice are unable to produce insulin, resulting in abnormally high blood sugar levels. These ongoing studies will test how well the device integrates into the mouse “patient” and will see if the device impacts the blood glucose levels in the mouse.

So far, Richard’s project has produced interesting data, though, as always, there are important remaining questions. One possible question is how well the device would function in a mouse with a fully functioning immune system. Richard’s current experiments are following the common technique of using immunocompromised mice, which can help simplify the complex biological system and help reduce noise in your initial data. Eventually, testing in a mouse with a functioning immune system will help determine if the device elicits any sort of immune response, which is not uncommon and would be important to understand prior to using it in humans. Fully aware of this, Richard and colleagues are developing ideas to prevent possible immune responses toward the device, including trying to make the device into an immune privileged zone by coating it with various molecules, like FasL or other immune modulating factors, which would help keep out unwanted immune cells.

Richard is in the midst of cutting-edge cell therapy research for type 1 diabetes, a disease for which there is no cure and a serious unmet medical need. His cell therapy approach using an implantable microporous device appears to be a potentially promising technique, and I’m excited to follow Richard’s work as he continues to generate exciting data.

Special thanks to:

Richard Youngblood, PhD grad student, Shea Lab, University of Michigan (youngblr@umich.edu)