Metabolic and Secretory Systems

The goal of this thrust is to develop the core technologies needed for tissue substitutes of metabolic and/or secretory function. An example of such a substitute is a bioartificial pancreas which is based on cells secreting insulin in response to physiologic glucose concentrations. To assist immune acceptance, cells are sequestered in semipermeable membranes allowing passage of small molecular weight nutrients and metabolites, including insulin, but excluding larger antibodies and cytotoxic cells of the host. We are pursuing the use of both allogeneic cells as well as the development of a somatic cell gene delivery approach involving autologous cells. For the latter, cells removed from the patient would be genetically engineered in vitro for glucose-responsive insulin secretion, then re-implanted into the patient for in situ insulin delivery.

Current GTEC Funded Projects

Cell technology research includes

• the genetic engineering of non-ß cells, such as hepatocytes, for insulin secretion and glucose responsiveness;

• the characterization of cell function under conditions prevailing in the construct pre- and post-implantation.

Construct technology research combines experimental and modeling studies and includes

• the development of improved immunoprotective membranes with defined transport properties;

• the establishment of design criteria for encapsulated cell systems so that cells remain viable and functional and constructs are rapidly responsive to glucose;

• the association of cells with glucose-responsive materials so as to develop hybrid constructs with improved secretion dynamics;

• the characterization of construct function in vitro using properly monitored and controlled bioreactors;

• the development of methods for construct preservation, cryopreservation;

• the use of non-invasive monitoring such as nuclear magnetic resonance (NMR) imaging and spectroscopic techniques for evaluating construct function non-invasively in vitro.

Integration into living systems research includes

• evaluating the effectiveness of genetically engineered autologous cells in restoring normoglycemia in streptozotocin rats and the importance of the insulin delivery site;

• studying the effectiveness of encapsulated allogeneic cells in restoring normoglycemia in streptozotocin and NOD mice and the implementation immune modulation strategies for prolonging the survival and function of implants;

• developing and characterizing immune modulation protocols for the survival and function of insulin-secreting cell allografts in non-human primates;

• establishing NMR imaging and spectroscopic methods for assessing construct function post-implantation in vivo.