A vascularized islet cell transplantation device for T1D therapy bypasses systemic immunosuppression

A coin-sized implantable device created by scientists at the Houston Methodist Institute’s Division of Nanomedicine could dramatically change the treatment of type 1 diabetes (T1D). A team led by Dr. Alessandro Grattoni, Chair of the Nanomedicine Division, delivered pancreatic islet cells and immunotherapies directly into a 3D-printed angiogenic transplantable cell homing and encapsulation (NICHE) device. When tested in animal models, NICHE implants restored healthy blood sugar levels and eliminated T1D symptoms for over 150 days. We also avoided severe side effects of anti-rejection therapy by administering immunosuppressive drugs only where the transplanted islet cells were present.

Reported development in Nature Communications (“A transplantable niche with local immunosuppression for pancreatic islet allografts achieves reversal of type 1 diabetes in ratsLead author Grattoni and colleagues say, “Overall, NICHE is a promising solution with the potential to transform the field of islet transplantation for the safe, long-term treatment of type 1 diabetes.” The researchers hope that further development will lead to clinical trials starting within his three years.

Type 1 diabetes is caused by an autoimmune reaction that destroys insulin-producing pancreatic islet cells. It can also cause kidney failure. Daily insulin injections are the most common treatment for T1D, but it remains difficult and cumbersome for patients to tightly control blood glucose levels. Additionally, in more severe cases, patients may require pancreas and kidney transplants. Alternatively, you may be eligible to harvest and process islet cells from a deceased pancreatic donor and then undergo islet cell transplantation (Clinical Islet Transplantation (CIT)). Transplanted into the liver of a T1D patient. “In CIT, isolated islets are transplanted into the portal circulation and passively engrafted into liver sinusoids,” the authors explain. “Because pancreatic islets provide dynamic glucose control, CIT significantly improves glycemic profiles, reduces hypoglycemic events, and reduces the progression of diabetes-related complications.”

However, although such transplants can help improve the patient’s condition, as with all organ transplants, one of the biggest challenges is the lifelong use of immunosuppressive drugs to avoid transplant rejection. It’s a necessity. Lifelong immunosuppression can make patients more susceptible to infections and increase the risk of certain types of cancer. Graft attrition associated with hypoxia is another important issue, the authors report. “The efficacy of islet transplantation for T1D management is limited by hypoxia-associated graft attrition and the need for systemic immunosuppression.”

Grattoni’s Nanomedicine Lab in Houston Methodist focuses on implantable nanofluidics-based platforms for controlled long-term drug delivery and cell transplantation to treat chronic diseases. Their newly described NICHE device, a flat, coin-sized device placed under the skin, consists of a cell reservoir for pancreatic islets and a surrounding drug reservoir for local immunosuppressive therapy. This device was developed to meet important criteria for long-term islet transplantation and therapeutic efficacy. These include “islet access to oxygen, nutrients, and metabolites to maintain function, evasion of the immune system to prevent rejection, and footprint to improve translatability and patient acceptability.” and reduced invasiveness”. The resulting platform, they claim, is the first to combine direct angiogenesis and local immunosuppression in a single implantable device for allogeneic islet transplantation and long-term T1D management. Direct angiogenesis is fundamental for supplying nutrients and oxygen to maintain viability of transplanted islet cells.

“The angiogenesis of the NICHE central cell reservoir is achieved by exploiting the pro-angiogenic properties of mesenchymal stem cell (MSC) hydrogels, while the integration of interconnected external drug reservoirs allows for vascularization through the nanoporous membrane. It enables the direct and local delivery of immunosuppressive agents to the cell reservoirs in which they are located,” they further explained. The team’s experiments confirmed that local immunosuppression prevented islet rejection without inducing systemic immunosuppression.

Tests with the device in animal models showed that allogeneic islets implanted within the prevascularized NICHE device were engrafted, revascularized, and functional, reversing diabetes in rats for over 150 days. it was done. “Of note, we confirmed that local immunosuppression prevents islet rejection without inducing toxicity or systemic immunosuppression,” the scientists said. “An important result of our study is that local immunosuppression for cell transplantation is effective,” he added Grattoni. “This device has the potential to change the paradigm of how patients are managed, and has the potential to significantly impact treatment efficacy and improvements in patient quality of life.”

The NICHE has a built-in port so it can be refilled with medication as needed. The ability to replenish NICHE technology enables long-term patient use. In the reported study, researchers found he refilled his drug reservoir every 28 days. It is comparable to other long-acting drugs clinically available for migraine prevention and HIV treatment, they say. Grattoni’s team is working to scale up his NICHE technology for clinical deployment, where he will only need to replenish the drug once every six months. Additionally, by altering the drug formula or concentration, the replenishment interval can be extended to once a year to coincide with regular doctor visits.

Grattoni and his collaborators aim to scale up their research in the next few years, with the goal of testing NICHE’s safety in humans in about three years.