Glucose-responsive materials for self-regulated insulin delivery

Achieving normal glycemic control in diabetic patients is nearly impossible given the pharmacokinetics after subcutaneous injection of commercial insulin. Glucose- regulated insulin delivery (GRID) would vastly improve glycemic control while reducing (i) the required frequency of subcutaneous injections and finger-stick glucose tests, (ii) the incidence of hypoglycemia and hyperglycemia, and (iii) the resulting nerve, kidney, retinal and cardiovascular complications associated with the disease. We have chosen to formulate a GRID system into a repeated dosage form capable of being administered through injection, inhalation, or oral routes to eliminate the need for surgery. In our particular system, dextran, a glucose-containing polymer, was crosslinked using the tetrafunctional glucose-binding protein, concanavalin A (Con A). Glucose then directly competed with the polymer for Con A binding sites, causing displacement of the polymer and disruption of the crosslinks. Through careful manipulation of dextran molecular weight (MW) and Con A/dextran crosslink ratio we have synthesized self-contained gels that erode at rates that depended directly on environmental glucose concentration. Since Con A binding affinity and glucose set-point (GSP) decreased from 25⁰C to 37⁰C, covalent mannosylation was required to increase binding affinity and minimize gel dissolution at glucose concentrations below 100 mg/dl. Hybrid gels constructed from varying weight ratios of mannosylated and unmodified dextrans further provided a convenient means for fine- tuning the GSP to closely match the physiological, glucose-dependent pancreatic -cell response.

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Chemical Engineering.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2004

Author dc:creator

• Zion, Todd C

Advisor dc:contributor.advisor

• Jackie Y. Ying.

• Chemical Engineering.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

en_US

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/28359

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/28359