Improving the bioartificial pancreas: Investigation of the effects of pro-survival and insulinotropic factor delivery and the development of PEGylated alginate microcapsules to support the function and survival of encapsulated islets and beta cells

Bioartificial pancreas;Diabetes;Alginate microcapsule;Islet;Beta-cell;CXCL12;SDF-1;GLP-1;PEG;Hypoxia;Exendin-4

Duncanson, Stephanie ; Sambanis, Athanassios Biomedical Engineering (Joint GT/Emory Department) Babensee, Julia Champion, Julie Temenoff, Johnna Safley, Susan ; Sambanis, Athanassios

University:Georgia Institute of Technology

Department:Biomedical Engineering (Joint GT/Emory Department)

关键词: Bioartificial pancreas;    Diabetes;    Alginate microcapsule;    Islet;    Beta-cell;    CXCL12;    SDF-1;    GLP-1;    PEG;    Hypoxia;    Exendin-4;   

Others  :  https://smartech.gatech.edu/bitstream/1853/54015/1/DUNCANSON-DISSERTATION-2014.pdf

美国|英语

来源: SMARTech Repository

【 摘 要 】

The development of a bioartificial pancreas (BAP) has the potential to substantially improve the treatment of insulin-dependent diabetes.Composed of insulin-secreting cells encapsulated in a hydrogel material, a BAP may provide superior glycemic regulation compared with conventional exogenous insulin-delivery therapies. Towards this goal, β- cells or islets encapsulated in alginate microcapsules remain a promising approach. Due to the limited supply of human islets, alternative cell sources are under investigation for incorporation into a BAP, including porcine islets and β- cell lines. Several challenges remain to clinical implementation, including loss of islet or β- cell function and viability following transplantation and host response to the transplanted microcapsules.The objective of this work was to evaluate strategies to improve a BAP by supporting the function and survival of encapsulated islets and β -cells.Towards this goal, two areas were explored: 1) the provision of pro-survival and insulinotropic factors, namely, CXCL12 and GLP-1 (or a GLP-1 analog, Exendin-4), to encapsulated islets and β-cells and 2) modification of the alginate microcapsule to confer long-term resistance to host cell adhesion.To achieve the first objective, methods to deliver both pro-survival and insulinotropic factors to a BAP were developed and their effects on encapsulated β-cells and porcine islets were studied, both in vitro and in vivo. Results demonstrate that delivery of pro-survival and insulinotropic factors is a promising strategy to prolong the survival and function of a BAP.To reduce host cell adhesion to the microcapsule, we employed covalent conjugation of PEG to the surface of alginate-PLL capsules to replace the un-crosslinked layer of alginate used in traditional alginate-PLL-alginate (APA) microcapsules.Results demonstrate that while PEGylation of alginate-PLL microcapsules initially reduced host cell adhesion over 2 weeks in vivo compared with APA capsules, the PEG coating did not provide long-term protection over 3 months.Taken together, these studies represent a multipronged approach towards improving the duration of BAP function, with the ultimate goal of advancing this technology to the clinic.