A Vascularized Tissue-Mimetic Platform for Modeling Pancreatic Islet Function and Disease
Abstract
This proposal focuses on the Topic Area “Diabetes” and specifically on “Research to design and implement disease in a dish and/or microfluidic models to model pancreatic islets to uncover pathogenesis and improve efficiency of drug discovery.” Diabetes is a metabolic diseases resulting from the loss or dysfunction of insulin-producing pancreatic beta cells leading to life-threatening complications and multi-organ failure, including blindness, cardiovascular disease, neuropathy, and kidney failure. Presently, ~29.1 million Americans (or 9.3% of the population) have diabetes, with an additional 86 million individuals affected by a pre-diabetic condition characterized by moderately high blood sugar levels and obesity. These numbers are projected to increase to ~50 million individuals 2030. Strikingly, the incidence of diabetes in military Service members has been estimated to be 4-5 times higher than that reported in the general population. The higher incidence of diabetes in military Service members appears to be related to the type of military service (deployment with combat assignment), mental health conditions, and posttraumatic stress disorders (PTSD). These facts underline the urgency to accelerate the pace of discovery of new treatments for this devastating disease. But how can new treatments be quickly discovered? Over the past half-century, studies focusing on the identification of causes for various diseases and testing of new drugs have been driven by the use of animal models. Although these models have led to important discoveries and testing of new treatments, a major limitation of experiments in vivo in live animals is that it is virtually impossible to directly study disease mechanisms in real time, as they occur in the body. Specifically, it has been difficult to “monitor live” the destruction of pancreatic beta cells by the immune system (like it occurs in type 1 diabetes) or the appearance of pancreatic beta cell malfunction that become apparent when the cells are exposed to high levels of glucose, saturated fatty acids, or cholesterol. In this regard, recent progress in bioengineering technologies has opened new opportunities for developing tissue-like microenvironments out of the body that recapitulate key features of tissues in living organisms. Here we propose to reconstruct an in vivo-like tissue microenvironment that promotes pancreatic islet vascularization and long-term function ex vivo, so to dissect how pancreatic islets are injured by certain insults. In pilot experiments, we tested the feasibility of developing this tissue-mimetic pancreatic islet-on-chip system to model mechanisms of islet injury and test therapies that may lead to the recovery of pancreatic islet function in diabetics. Unique innovative features of the work that we are proposing include (1) the ability to reconstruct near-physiologic pancreatic islet tissue in a microfluidic chip that has the size of half a credit card, including a networks of blood vessel-like tubular structures through which the islets can “sense” circulating levels of glucose and respond to it by secreting insulin as in vivo. (2) An additional innovative feature is the possibility to model in this system, in real time and long term, the toxic effects of high concentrations of glucose and saturated fats on the islets, as well as their ability to recover from these toxic effects. (3) Finally, this system will allow us to test whether there are populations of islet cells that can regenerate following injury and whether chronic administration of pro-regenerative drugs is safe at preserving islet function. We anticipate that results from the proposed work will establish the foundation for future research projects exploiting the power of this new tissue-mimetic pancreatic islet-on-chip system for testing anti-diabetic therapies in humans. Building on preliminary proof-of-principle tests, and based on the predicted properties and capabilitie
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810065
Entities
People
- Laura Crisa
Organizations
- United States Army
- University of Washington