Islets surface modification prevents blood-mediated inflammatory responses.
Transplantation of islets of Langerhans (islets) is a promising technique for treating insulin-dependent diabetes mellitus (type I). One unresolved issue is early graft loss due to inflammation triggered by blood coagulating on the surface of islets after transplantation into the portal vein. Here, we describe a versatile method for modifying the surface of islets with an ultrathin membrane carrying the fibrinolytic enzyme urokinase or the anticoagulant heparin. The surface of islets was modified with a poly(ethylene glycol)--phospholipid conjugate bearing a biotin group (biotin-PEG-lipids, PEG MW: 5000). Biotin-PEG-lipids were anchored to the cell membranes of islets, and the PEG-lipid layer on the islets was further covered by streptavidin and biotin-bovine serum albumin conjugate using a layer-by-layer method. The surface was further activated with oxidized dextran. Urokinase was anchored to the islets through Schiff base formation. Heparin was anchored to the islets through polyion complex formation between anionic heparin and a cationic protamine coating on the islets. No practical islet volume increase was observed after surface modification, and the modifications did not impair insulin release in response to glucose stimulation. The anchored urokinase retained high fibrinolytic activity, which could help to improve graft survival by preventing thrombosis on the islet surface.
Department of Nano-Medicine Merger Education Unit, Graduate School of Engineering, Kyoto University, and Institute for Frontier Medical Sciences, Kyoto University, 53 Kawara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
Yuji
Y
Teramura
Hiroo
H
Iwata
D000818:Animals; D000925:Anticoagulants / Q000378:metabolism; D001710:Biotin / Q000378:metabolism; D001777:Blood Coagulation; D002417:Cattle; D006224:Cricetinae; D004800:Enzymes, Immobilized / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000494:pharmacology; D006493:Heparin / Q000378:metabolism; D007249:Inflammation / Q000097:blood* / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000378:metabolism; D019809:Streptavidin / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D000925:Anticoagulants; D004800:Enzymes, Immobilized; D007328:Insulin; D012710:Serum Albumin, Bovine; D001710:Biotin; D006493:Heparin; D019809:Streptavidin; D014568:Urokinase-Type Plasminogen Activator; D005947:Glucose