Recent research published in Nature Biomedical Engineering has shown a way to dramatically improve the feasibility of transplanting therapeutic cells, particularly pancreatic islet cells, while protecting them from the recipient’s immune response.
Shielding transplanted cells from the immune system
Because the functions of the pancreas are simple relative to other organs, most tissue engineering attempts to emulate the organ have also taken a simplistic approach. Rather than trying to regenerate a whole organ and the complex structure that accompanies it, most research has focused on the functional beta cells that become dysfunctional in patients with diabetes. While these beta cells can be isolated and manufactured, form clusters known as islets, and secrete insulin when transplanted, the recipient’s immune response ultimately limits their success. In type 1 diabetes, the patient’s immune system mistakenly attacks their own beta cells. In type 2 diabetes, the patient’s beta cells are dysfunctional and so cells from a different patient (non-autologous) must be used, which also elicits an immune response.
Much research has been done to develop implants that house the beta cells and protect them from the immune system while still allowing incoming nutrients and outgoing insulin. While this has been successful by using extremely small pore sizes that immune cells cannot penetrate, the body has other defense mechanisms. A fibrotic response can still wall off the entire implant, preventing nutrients from getting in and insulin from getting out. Researchers at MIT have recently demonstrated a material capable of preventing this fibrosis and allowing for long-term survival of the implant. 
First, the researchers demonstrated in vitro the ability of several cell types to survive, proliferate, and excrete therapeutic molecules, including fibroblasts, muscle cells, and kidney cells. They then optimized for pore size using kidney cells genetically primed to excrete erythropoietin (EPO) and placed the implants in the central gut (intraperitoneal) space of healthy mice. With 3 µm pores, both T-cells and macrophages from the immune system were able to penetrate the device. Interestingly, some macrophages were able to penetrate 1 µm pores, but not T cells, a phenomenon that has not been demonstrated before. Infiltration of these cells resulted in fewer kidney cells and less circulating EPO in the mice that received the implants. Pores of 0.8, 0.6, and 0.4 µm did not allow for immune cell infiltration but did support kidney cell survival and EPO excretion.
A new anti-fibrotic coating to prevent encapsulation
Next, the researchers tested five anti-fibrotic coatings on different devices along with an uncoated device as a control group. Two of the coatings showed no improvement, two moderately reduced fibrotic encapsulation of the device, and one showed almost no fibrotic encapsulation at all. The successful coating was a small molecule known as tetrahydropyran phenyl triazole (THPT). Kidney cells in the THPT device increased their EPO production up to 30 days and continued their therapeutic benefit with only a mild decrease during the length of the study: an extremely impressive 130 days.
A successful application in healthy mice using a robust cell line is one thing, but the researchers took their experiments one step further by implanting rat beta cells into mice with STZ-induced diabetes. In these mice, the implant maintained normal blood glucose levels indistinguishable from those of healthy mice without any immune suppression or additional therapeutic drugs. In implants without the THPT coating, these effects started to wear off at about 20 days. However, with the THPT coating, the effects of the implant were maintained for a median of 75 days. Afterwards, the implants were able to safely be removed surgically.
For >130 days, the device supported human cells engineered to secrete erythropoietin in immunocompetent mice, as well as transgenic human cells carrying an inducible gene circuit for the on-demand secretion of erythropoietin. Pancreatic islets from rats encapsulated in the device and implanted in diabetic mice restored normoglycaemia in the mice for over 75 days. The biocompatible device provides a retrievable solution for the transplantation of engineered cells in the absence of immunosuppression.
This study, particularly the researchers’ THPT coating, demonstrates considerable improvement in the delivery of therapeutic cells that require protection from the recipient’s immune system. While the most obvious application is to supplement the function of the pancreas (for type 1 diabetes in particular), this technology is not specific to the cell types tested in this study and could be utilized in a broad range of potential therapies. Such cellular factories of therapeutic compounds could be highly beneficial because they can react to their environment, such as beta cells reacting to glucose. Still, more research will be needed before these devices are ready for the clinic. The immune response in humans to THPT may vary from that of mice, and additional work will be needed to further extend the life of these implants in vivo.
 Bose, S., Volpatti, L.R., Thiono, D., Yesilyurt, V., McGladrigan, C., … Langer, R., & Anderson, D.G. (2020). A retrievable implant for the long-term encapsulation and survival of therapeutic xenogeneic cells. Nature Biomedical Engineering, 4, 814-826.