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Nat Biomed Eng. 2018 Nov;2(11):810-821. doi: 10.1038/s41551-018-0275-1. Epub 2018 Aug 13.

Alginate encapsulation as long-term immune protection of allogeneic pancreatic islet cells transplanted into the omental bursa of macaques.

Bochenek MA1,2,3,4,5, Veiseh O3,4,5,6,7, Vegas AJ3,4,5,8, McGarrigle JJ1,9, Qi M1, Marchese E1, Omami M1, Doloff JC3,4,5, Mendoza-Elias J1,2, Nourmohammadzadeh M1,2,10, Khan A1, Yeh CC1, Xing Y1,2,11, Isa D1,9, Ghani S1,9, Li J3,4,5,6,7, Landry C3,4,5, Bader AR3,4,5, Olejnik K3,4,5,6,7, Chen M3,4,5, Hollister-Lock J12, Wang Y1,2,11, Greiner DL13, Weir GC12, Strand BL14, Rokstad AMA15,16, Lacik I17, Langer R3,4,5,18,19,20, Anderson DG21,22,23,24,25,26, Oberholzer J27,28,29.

Author information

1
Division of Transplantation, Department of Surgery, University of Illinois at Chicago, Chicago, IL, USA.
2
Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, USA.
3
David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
4
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
5
Department of Anesthesiology, Boston Children's Hospital, Boston, MA, USA.
6
Sigilon Therapeutics, Inc., Cambridge, MA, USA.
7
Department of Bioengineering, Rice University, Houston, TX, USA.
8
Chemistry Department, Boston University, Boston, MA, USA.
9
CellTrans Inc., Chicago, IL, USA.
10
Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC, USA.
11
Department of Surgery and Biomedical Engineering, University of Virginia, Charlottesville, VA, USA.
12
Section on Islet Cell and Regenerative Biology, Research Division, Joslin Diabetes Center, Boston, MA, USA.
13
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
14
Department of Biotechnology and Food Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
15
Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
16
Centre of Obesity, Clinic of Surgery, St. Olavs University Hospital, Trondheim, Norway.
17
Polymer Institute, Slovak Academy of Sciences, Bratislava, Slovakia.
18
Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA.
19
Division of Health Science Technology, Massachusetts Institute of Technology, Cambridge, MA, USA.
20
Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
21
David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.
22
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.
23
Department of Anesthesiology, Boston Children's Hospital, Boston, MA, USA. dgander@mit.edu.
24
Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA. dgander@mit.edu.
25
Division of Health Science Technology, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.
26
Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.
27
Division of Transplantation, Department of Surgery, University of Illinois at Chicago, Chicago, IL, USA. JO5JE@hscmail.mcc.virginia.edu.
28
Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, USA. JO5JE@hscmail.mcc.virginia.edu.
29
Department of Surgery and Biomedical Engineering, University of Virginia, Charlottesville, VA, USA. JO5JE@hscmail.mcc.virginia.edu.

Abstract

The transplantation of pancreatic islet cells could restore glycaemic control in patients with type-I diabetes. Microspheres for islet encapsulation have enabled long-term glycaemic control in diabetic rodent models; yet human patients transplanted with equivalent microsphere formulations have experienced only transient islet-graft function, owing to a vigorous foreign-body reaction (FBR), to pericapsular fibrotic overgrowth (PFO) and, in upright bipedal species, to the sedimentation of the microspheres within the peritoneal cavity. Here, we report the results of the testing, in non-human primate (NHP) models, of seven alginate formulations that were efficacious in rodents, including three that led to transient islet-graft function in clinical trials. Although one month post-implantation all formulations elicited significant FBR and PFO, three chemically modified, immune-modulating alginate formulations elicited reduced FBR. In conjunction with a minimally invasive transplantation technique into the bursa omentalis of NHPs, the most promising chemically modified alginate derivative (Z1-Y15) protected viable and glucose-responsive allogeneic islets for 4 months without the need for immunosuppression. Chemically modified alginate formulations may enable the long-term transplantation of islets for the correction of insulin deficiency.

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