Document text
Principal Investigator: Christopher Alan Fraker
Organization: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
Fiscal Year: 2024
Award: $390,726
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
PROJECT SUMMARY
The past fifty years have seen substantial advances in the field of encapsulation of
insulin producing tissues for the treatment of Type 1 Diabetes Mellitus. Persistent
obstacles and limitations of the current technologies have prevented translation of these
results to the clinical realm. Multiple groups are now poised for clinical translation, but
still lack adequate, easily retrievable delivery devices. One major obstacle is the
limitation of tissue loading in conventional encapsulation that results from the high
metabolic demand of native islets/SC-β and the concomitant mass transport limitations
of most encapsulation materials. Importantly, native islets experience oxygen and
nutrient deficit in loading densities greater than 1.5 to 2% v/v in standard alginate
microcapsules. In smaller capsules of alternate materials, mass transfer is impaired due
to monomer structure and cross-linking strategies. This adversely affects the benefit
afforded by the smaller diffusive distance.
Fundamental aspects of cell encapsulation must be reexamined. Research
efforts have been focused on the in vivo application where reduction in device geometry
is crucial to clinical success through the reduction of oxygen transfer distances and
overall biomaterial/graft volume. There has been little study of pre-transplant culture
where hypoxia and loss of viability/function are the result of cell proximity to the plastic
basal surface. This causes cell death and results in antigen shedding. In vivo, the
opposite holds true where larger geometry results in increased chance of hypoxia at
clinically relevant loading densities. The central hypothesis of this proposal is that
impaired oxygen mass transfer results in increased hypoxia/anoxia, loss of
function, apoptosis and antigen shedding. This proposal seeks to address these
obstacles through the following specific aims: 1.) we will determine the effect of capsule
geometry and pre-implant culture methods on encapsulated islet/SC-β viability, function,
antigen shedding and in-vitro inflammatory response from co-culture with macrophages.
2.) we will employ oxygen carrying perfluorocarbon nanoemulsions in islet encapsulation
devices in immune-deficient, immune competent and autoimmune mouse models
(BALB/C, C57BL/6, NOD-SCID, NOD) with chemical induction (STZ) of diabetes to
ascertain the additive effect of each on engraftment and restoration of normoglycemia.
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Terms: <Acceleration><Address><Affect><Alginates><Anoxia><Antigens><Apical><Apoptosis><Apoptosis Pathway><Attention><Autoimmune><BALB C Mouse><BALB/c><Biocompatible Materials><Biomaterials><Blood Vessels><Body Tissues><Brittle Diabetes Mellitus><Capsules><Cell Aggregation><Cell Body><Cell Death><Cell Function><Cell Physiology><Cell Process><Cell Survival><Cell Viability><Cells><Cellular Function><Cellular Physiology><Cellular Process><Chemicals><Clinical><Co-culture><Cocultivation><Coculture><Coculture Techniques><Computer Models><Computerized Models><D-Glucose><Data><Devices><Dextrose><Diabetes Mellitus><Diffusion><Disease><Disorder><Encapsulated><Engraftment><Environment><Epidemiology><Equilibrium><Fluorocarbons><Functional impairment><Gases><Geometry><Glucose><Goals><Health Care Systems><Healthcare Systems><Hour><Humulin R><Hypoxia><Hypoxic><IDDM><Immunocompetent><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Impairment><Implant><In Vitro><Inbred BALB C Mice><Incidence><Individual><Inflammatory><Inflammatory Response><Innate Immune Response><Insulin><Insulin-Dependent Diabetes Mellitus><Intervention><Intervention Strategies><Investigation><Islands of Langerhans Transplantation><Islands of Pancreas Transplantation><Islets of Langerhans Grafting><Islets of Langerhans Transplantation><Juvenile-Onset Diabetes Mellitus><Ketosis-Prone Diabetes Mellitus><Length of Life><Longevity><Macrogols><Macrophage><Metabolic><Methodology><Methods><Mice><Mice Mammals><Microcapsules drug delivery system><Murine><Mus><Mφ><Novolin R><Nutrient><O element><O2 element><Oxygen><Oxygen Deficiency><Pancreatic Islets Transplantation><Particle Size><Pathway interactions><Patients><Perfluorocarbons><Performance><Permeability><Polyethylene Glycols><Polyethylene Oxide><Polyethyleneoxide><Polyoxyethylenes><Procedures><Production><Programmed Cell Death><Public Health><Regular Insulin><Research><Research Priority><Role><STZ><Streptozocin><Streptozotocin><Structure><Study models><Subcellular Process><Sudden-Onset Diabetes Mellitus><Surface><System><T1 DM><T1 diabetes><T1D><T1DM><Technology><Testing><Time><Tissue Transplantation><Tissues><Translations><Transplantation><Type 1 Diabetes Mellitus><Type 1 diabetes><Type I Diabetes Mellitus><Work><Zanosar><autologous islet transplantation><balance><balance function><biological material><capsule><clinical relevance><clinical translation><clinically relevant><clinically translatable><co-morbid><co-morbidity><comorbidity><computational modeling><computational models><computer based models><computerized modeling><cost><crosslink><density><diabetes><diffused><diffuses><diffusing><diffusions><epidemiologic><epidemiological><experience><hypoimmunity><immune competent><immune deficiency><immune suppression><immune suppressive activity><immune suppressive function><immunodeficiency><immunogen><immunosuppressive activity><immunosuppressive function><immunosuppressive response><improved><in vivo><insulin dependent diabetes><insulin dependent type 1><interventional strategy><islet><islet auto transplantation><islet beta cell transplantation><islet cell transplant><islet cell transplantation><islet transplantation><juvenile diabetes><juvenile diabetes mellitus><ketosis prone diabetes><loss of function><microcapsule><monomer><mouse model><murine model><nano emulsion><nanoemulsion><necrocytosis><oxygen transport><pathway><prevent><preventing><response><restoration><social role><success><translation><transplant><type I diabetes><type one diabetes><vascular>