Article by Diogo Teles, Roberta Lock, & Richard Zhuang
Device for Transplanting Therapeutic Human Cells
A retrievable implant for the long-term encapsulation and survival of therapeutic xenogeneic cells, Nature Biomedical Engineering, 2020
Suman Bose et al., Daniel G. Anderson Lab
The transplantation of therapeutic cells is a promising option in the treatment of several chronic diseases like type 1 diabetes and chronic kidney disease. In both diseases, the patient’s organs cannot produce important hormones (insulin and erythropoietin, respectively) as they are supposed to. A promising treatment option would be to transplant cells from a healthy donor to function in place of the diseased cells of the patient. However, the major barrier to doing this is that transplanted cells and devices can be attacked by the host’s immune system. To overcome this, different technologies have been developed to provide a safe option for their transplantation without the need for long-term suppression of the patient’s entire immune system. While several encapsulation methods have been studied over the years, there remains a need for a device which does not provoke a foreign body response. Now, a team at Massachusetts Institute of Technology (MIT) has reported a biocompatible device with a chemically modified surface for the long-term transplant of therapeutic cells in the absence of immunosuppression.
What did these researchers do?
The researchers developed an implantable and retrievable device for the transplantation of therapeutic cells which comprises two main components: a reservoir for the therapeutic cells, and a thin porous polymer membrane. The membrane has the optimal pore size to hold the therapeutic cells inside the device, preventing its invasion by the host’s immune cells, while still allowing for the diffusion of oxygen, nutrients, and secreted factors like hormones. This device is also coated with the small molecule tetrahydropyran phenyl triazole (THPT), which prevents cell overgrowth and fibrosis.
They showed the applicability of this technology by encapsulating human kidney cells and rat pancreas cells in several devices and transplanting them in mice with functional immune systems. Animals transplanted with devices containing kidney cells that were bioengineered to produce erythropoietin — a hormone that drives red blood cell production — presented increased serum levels of erythropoietin and red blood cells, which decreased after the removal of the device. Other devices encapsulating rat pancreatic cells were transplanted into diabetic mice. The blood glucose levels of these animals normalized rapidly after the device’s implantation, a process regulated by insulin.
Implantable cell encapsulation device by D. Anderson Lab
Why is this important?
While implanting cells is a promising solution to many chronic diseases, when cells from a healthy donor are directly implanted, they can be attacked and killed by the host's immune system. While cell-encapsulating devices overcome this issue, current cell-encapsulating devices incite a foreign body response. The formation of a fibrotic tissue layer around the implant stops transport of oxygen, nutrients, and secreted factors, ultimately causing implant failure. There is a need for a device that can maintain therapeutic cells in the body over long periods of time, without triggering such a response. A device like this overcomes both issues allowing the therapeutic cells to stay viable and functional for up to several months after transplant.
How did the researchers do this?
The team at MIT tested membranes with different pore sizes to find one able to block direct access to the therapeutic cells by harmful immune cells, but still allowing for the diffusion of oxygen, nutrients, and the secreted therapeutic factors. They found that membranes with a pore size of 3 µm resulted in the escape of the encapsulated cells and infiltration by immune cells, with loss of the transplanted cells, whereas devices with 0.8 µm or smaller pores completely prevented the infiltration of the devices by immune cells. They also tested different coatings in order to minimize the fibrotic response and to enhance the biocompatibility of the device. Results showed that devices coated with THPT best mitigated the fibrotic response over long periods.
What comes next?
This is a promising approach for the delivery of therapeutic cells, but some challenges and questions remain:
How long do the device and encapsulated cells survive in vivo? The team demonstrated encapsulated rat islets were capable of restoring physiological blood glucose levels for several months in diabetic mice. If this technology is going to be used in humans, the device needs to stay functional for longer periods of time. Do old devices need to be replaced with newer ones over time? Or is there a way to replenish the therapeutic cells to extend its longevity?
How permeable should the membrane be? Membranes with different pore sizes allow the infiltration of different immune cells. Preliminary studies have shown macrophages have a role in graft repair and protection, and might also be beneficial for pancreatic islet transplantation. Future studies should investigate how immune cells with a beneficial role could be recruited to the graft without rejection.