Restoring Pancreatic Endocrine Function via Autologous Islet Transplantation to the Omentum
Abstract
Chronic pancreatitis is inflammation of the pancreas that impairs a patient’s ability to digest food and make pancreatic hormones. When medical therapy and standard surgical management fail to provide relief to those patients, total pancreatectomy (TP), that is the removal of the entire pancreas, is the only way to relieve the pain. After TP, the pancreatic islets that are responsible to produce insulin and control blood glucose, will be isolated from the removed pancreas and transplanted back to the same patient by infusion to the liver portal vein. Instead of developing insulin-dependent diabetes following a total pancreatectomy, the patients will still be able to manage blood sugar as prior to the removal of the pancreas. However, the liver is not an ideal location for islet transplantation because it limits the total number of islets that can be transplanted and presents a hostile oxidative environment for the survival of the transplanted islets. To address this critical problem, we propose to use the omentum, which is the fat tissue surrounding abdominal organs, as the new islet transplantation site and to use an antioxidant macromolecule, poly (polyethylene glycol citrate-co-N isopropyl acrylamide) or PPCN, to protect the islets from oxidative stress during transplantation. We have previously shown the safety and efficacy of pancreatic islet transplantation using PPCN to the abdominal fat pads in mice successfully. In the current study, we propose to use the rhesus macaque, a nonhuman primate (NHP) that is physiologically similar to humans, as the animal model to demonstrate the safety and efficacy of this idea for pancreatic islet transplantation. Firstly, we will test the safety of the antioxidant macromolecule PPCN without islets by implanting PPCN to the omentum of rhesus macaques and comparing the results of tissue and blood response to animals that receive platelet-rich plasma (PRP) implanted to the omentum. PRP has been used in clinical trials to fix islets to the omentum, but due to the variable nature of PRP, results are unpredictable. We will monitor the health conditions of the animals for up to 90 days, after which the animals will be sacrificed and their omentum tissues harvested for histological assessment of tissue response to the transplanted materials. In addition, the pancreases of the same animals will be harvested and processed for islet isolation. The protective effect of PPCN will be demonstrated by assessing whether it can promote NHP islet survival and function in vitro, as well as maintain blood glucose control in vivo with mice that have a depleted immune system (referred to as nude mice). Next, we will assess the safety and efficacy of autologous islet transplantation with PPCN to the omentum of NHPs in a manner that replicates the intended clinical procedure in humans. We will perform TP, isolate islets from the rhesus macaque’s pancreas, add them to PPCN or the clinically relevant control autologous PRP, and deliver them to the grater omentum of the same animal during in one surgery session. The animals will be routinely monitored for their health conditions, especially their ability to control blood glucose. Six months post-surgery, the animals will be euthanized and all of the major organs will be evaluated for signs of adverse effect towards the islet transplantation. Chronic pancreatitis is a devastating condition that impacts the quality of life of our Veteran and civilian population alike. With the increased rate of diabetes due to exposure to Agent Orange, and reported higher rates of excessive alcohol consumption, a risk factor for chronic pancreatitis, in the Veteran population, therapies that are able to treat this disease will be of utmost importance to the military. Although not a disease that impacts a large percentage of the population, the healthcare costs involved to treat the disease and the highly negative impact on the quality of life of the patient w
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910230
Entities
People
- Guillermo Ameer
Organizations
- Northwestern University
- United States Army