Microencapsulation of cells, including islets, within stable ultra-thin membranes of maleimide-conjugated PEG-lipid with multifunctional crosslinkers.
The encapsulation of islets of Langerhans (islets) and insulin-secreting cells within a semi-permeable membrane has been suggested as a safe and simple technique for islet transplantation to attenuate early graft loss and avoid immunosuppressive therapy. The total volume of these implants tends, however, to increase upon encapsulation of the islets and cells within the polymer membrane, limiting transport between encapsulated cells and the surrounding tissue. Ultra-thin membranes could potentially overcome these diffusion limitations to provide for clinically applicable implants. Here we propose a method to encapsulate islets and cells within a stable ultra-thin polymer membrane using poly(ethylene glycol)-conjugated phospholipid bearing a maleimide group (Mal-PEG-lipids) and multiple interactive polymers (e.g., 4-arm PEG-Mal and 8-arm PEG-SH). When Mal-PEG-lipids were added to islet and cell suspensions, spontaneous incorporation into a cell surface occurred from the micelles at an equilibrium state. The addition of 4-arm PEG-Mal and 8-arm PEG-SH to the mixture induced a substantial increase in the membrane thickness because a number of Mal-PEG-lipid micelles were involved in the membrane formation at the micrometer level. No appreciable increase in islet volume was observed after microencapsulation by this method. Microencapsulation of islets with the polymer membranes, which showed semi-permeability, did not impair insulin release in response to glucose stimulation, even after 7 days. The polymer membrane structure surrounding the islets and cells was well maintained for at least 30 days. In addition, the membrane formed showed much lower thrombogenicity and inhibited complement activation upon exposure to human whole blood and serum.
Department of Immunology, Genetics and Pathology, Uppsala University, Sweden. yuji.teramura@igp.uu.se
Yuji
Y
Teramura
Oommen P
OP
Oommen
Johan
J
Olerud
Jöns
J
Hilborn
Bo
B
Nilsson
D000818:Animals; D001081:Apyrase / Q000378:metabolism; D002462:Cell Membrane / Q000737:chemistry; D018914:Cells, Immobilized / Q000737:chemistry*; D042783:Endothelial Cells / Q000737:chemistry / Q000166:cytology; D004800:Enzymes, Immobilized / Q000737:chemistry; D004912:Erythrocytes / Q000737:chemistry / Q000166:cytology; D006085:Graft Survival; D006801:Humans; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology*; D016381:Islets of Langerhans Transplantation / Q000379:methods; D008055:Lipids / Q000032:analysis / Q000737:chemistry*; D008297:Male; D008301:Maleimides / Q000032:analysis / Q000737:chemistry*; D008422:Materials Testing; D051379:Mice; D008810:Mice, Inbred C57BL; D010539:Permeability; D010743:Phospholipids / Q000032:analysis / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000032:analysis / Q000737:chemistry*; D011817:Rabbits; D013552:Swine; D013917:Thrombin / Q000378:metabolism
D004800:Enzymes, Immobilized; D007328:Insulin; D008055:Lipids; D008301:Maleimides; D010743:Phospholipids; C043592:maleimide; D011092:Polyethylene Glycols; D013917:Thrombin; C478632:Thrombogen; D001081:Apyrase