Recent advances in biomaterial science suggest opportunities to create synthetic niches for islet delivery that not only provide a physical barrier to permit short-term islet survival, but a biologically-controlled microenvironment that actively promotes long-term islet survival and function while biochemically modulating the local effects of the immune response. We hypothesize that a synthetic poly(ethylene glycol) (PEG) hydrogel niche, modified with critical extracellular matrix molecules to promote islet function and biological signals to suppress cell damage from stresses of the immune system, will support the long-term survival and function of transplanted islets. To test this hypothesis, gel niches that introduce both cell-cell and cell-matrix interactions will be synthesized, and functions critical to the overall success of islet transplantation therapies will be monitored: cell survival and metabolic activity, insulin secretion in response to glucose and other stimuli, and analysis of intracellular events that translate these extracellular stimuli into insulin release, such as intracellular calcium concentration (Aim 1). Through these experiments, we will identify `permissive' hydrogel chemistries, defined as ones that support islet survival and function over the course of 1 month in vitro. Aim 2 will test the ability of these permissive formulations to support islet function under physiological stress. Activated islet-specific T cell lines will be used in co-culture with the capsules to evaluate the immunoprotective capabilities of the PEG capsule. The biophysical properties (e.g., crosslinking density) of the gels will be varied, and the relative role of hypoxia will be examined. With this understanding, these permitting gel formulations will be further modified with immune modulatory antibodies and enzymes and anti-inflammatory anti-oxidative enzymes to establish new strategies to actively promote islet function and long-term survival by locally suppressing the effects of the cells of the host immune and inflammatory responses. These studies build on the base of knowledge gained from Aim 2, which identifies the cellular stresses that are most pressing and provides the directional framework for selected functional modifications of the capsule (Aim 3). Finally, the effectiveness of the `promoting' gel carriers that support and protect islet survivability and function will then be tested in a diabetic animal model (Aim 4).This proposal aims to prepare biomaterial devices that incorporate signals to actively promote the function of insulin-producing cells and improve the performance of devices transplanted into diabetic patients. If successful, this strategy will prolong the duration and function of transplanted pancreatic tissue without the need for life-long administration of immunosuppressive drugs.

R01DK076084

2008-01-07

2013-12-31