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Encapsulation of pancreatic islets has been proposed and investigated for over the past three decades to eliminate the need for immunosuppressants. A wide variety of materials have been tested for microencapsulation in animal models and some materials have been shown to provide immunoprotection. Despite the initial success of microcapsules in NHP models, the combined use of islet transplantation (allograft) and microencapsulation has not been fully successful in clinical trials. CellTrans research in this area focuses on how to improve encapsulation technique and islet function, explore a non-human primate model to test material biocompatibility and in vivo long-term graft function, aiming at clinical application. Through our research, we have gained a deep understanding of biocompatibility of alginate for encapsulation and islet functionality post encapsulation. Additionally, we developed a novel method to implant microencapsulated islets in a non-human primate model that significantly reduced capsule surface overgrowth and increased islet graft survival.

Alginate encapsulation as long-term immune protection of allogeneic pancreatic islet cells transplanted into the omental bursa of macaques. Matthew Bochenek, Omid Veiseh, Arturo Vegas , James McGarrigle, Meirigeng Qi, Enza Marchese, Mustafa Omami, Joshua Doloff, Dr. Joshua Mendoza-Elias, Mohammad Nourmohammadzadeh, Arshad Khan , Chun-Chieh Yeh, Yuan Xing, Douglas Isa, Sofia Ghani, Jie Li , Casey Landrey, Andrew Bader, Karsten Olejnik, Michael Chen, Jennifer Hollister-Lock, Yong Wang, Dale Greiner, Gordon Weir, Berit Løkensgard Strand, Anne Mari Rokstad, Igor Lacik, Robert Langer, Daniel Anderson and Jose OberholzerNature Biomedical Engineering. August, 2018 10.1038/s41551-018

Size- and shape-dependent foreign body immune response to materials implanted in rodents and non-human primates Omid Veiseh, Joshua C. Doloff, Minglin Ma, Arturo J. Vegas, Hok Hei Tam, Andrew Bader, Jie Li, Erin Langan, Jeffrey Wyckoff, Whitney S. Loo, Siddharth Jhunjhunwala, Alan Chiu, Sean Siebert, Katherine Tang, Jennifer Hollister-Lock, Stephanie Aresta-Dasilva, Matthew Bochenek, Joshua Mendoza-Elias, Yong Wang, Merigeng Qi, Danya M. Lavin, Nimit Dholakia, Raj Thakrar, Gordon C. Weir, Jose Oberholzer, Dale L. Greiner, Robert Langer, and Daniel G. Anderson. Nature Materials. April, 2015. PMID: 25985456

A recommended laparoscopic procedure for implantation of microcapsules in the peritoneal cavity of non-human primates Qi M, Lacik I, Kolláriková G, Strand BL, Formo K, Wang Y, Marchese E, Mendoza-Elias JE, Kinzer KP, Gatti F, Paushter D, Patel S, Oberholzer JJ Surg Res. 2011 Jun 1;168(1):e117-23.  PMID: 21435661

Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates. Vegas AJ, Veiseh O, Doloff JC, Ma M, Tam HH, Bratlie K, Li J, Bader AR, Langan E, Olejnik K, Fenton P, Kang JW, Hollister-Locke J, Bochenek MA, Chiu A, Siebert S, Tang K, Jhunjhunwala S, Aresta-Dasilva S, Dholakia N, Thakrar R, Vietti T, Chen M, Cohen J, Siniakowicz K, Qi M, McGarrigle J, Lyle S, Harlan DM, Greiner DL, Oberholzer J, Weir GC, Langer R, Anderson DG. Nature Biotechnology, 2016 Jan 25. PMID: 26807527

Long-term glycemic control using polymer-encapsulated human stem cell-derived beta cells in immune-competent mice. Vegas AJ, Veiseh O, Gürtler M, Millman JR, Pagliuca FW, Bader AR, Doloff JC, Li J, Chen M, Olejnik K, Tam HH, Jhunjhunwala S, Langan E, Aresta-Dasilva S, Gandham S, McGarrigle JJ, Bochenek MA, Hollister-Lock J, Oberholzer J, Greiner DL, Weir GC, Melton DA, Langer R, Anderson DG. Nature Medicine. 2016 Mar;22(3):306-11. doi: 10.1038/nm.4030. Epub 2016 Jan 25. PMC4825868.

Colony stimulating factor-1 receptor is a central component of the foreign body response to biomaterial implants in rodents and non-human primates. Doloff JC, Veiseh O, Vegas AJ, Tam HH, Farah S, Ma M, Li J, Bader A, Chiu A, Sadraei A, Aresta-Dasilva S, Griffin M, Jhunjhunwala S, Webber M, Siebert S, Tang K, Chen M, Langan E, Dholokia N, Thakrar R, Qi M, Oberholzer J, Greiner DL, Langer R, Anderson DG. Nature Materials. 2017 Jun;16(6):671-680. doi: 10.1038/nmat4866. Epub 2017 Mar 20. PubMed PMID: 28319612; PubMed Central PMCID: PMC5445003.

Structural changes in alginate-based microspheres exposed to in vivo environment as revealed by confocal Raman microscopy. Kroneková Z, Pelach M, Mazancová P, Uhelská L, Treľová D, Rázga F, Némethová V, Szalai S, Chorvát D, McGarrigle JJ, Omami M, Isa D, Ghani S, Majková E, Oberholzer J, Raus V, Šiffalovič P, Lacík I. Sci Rep. 2018 Jan 26;8(1):1637. doi: 10.1038/s41598-018-20022-y. PubMed PMID: 29374272; PubMed Central PMCID: PMC5785987.

Alginate microbeads are coagulation compatible, while alginate microcapsules activate coagulation secondary to complement or directly through FXII.  Gravastrand C, Hamad S, Fure H, Steinkjer B, Ryan L, Oberholzer J, Lambris JD, Lacík I, Mollnes TE, Espevik T, Brekke OL, Rokstad AM. Acta Biomater. 2017 Aug;58:158-167. doi: 10.1016/j.actbio.2017.05.052. Epub 2017 May 30. PubMed PMID: 28576714; PubMed Central PMCID: PMC5607061.

Beneficial effects of coating alginate microcapsules with macromolecular heparin conjugates-in vitro and in vivo study. Vaithilingam V, Kollarikova G, Qi M, Larsson R, Lacik I, Formo K, Marchese E, Oberholzer J, Guillemin GJ, Tuch BE. Tissue Eng Part A. 2014 Jan;20(1-2):324-34. doi: 10.1089/ten.TEA.2013.0254. Epub 2013 Oct 2. PubMed PMID: 23971677.

Binding and leakage of barium in alginate microbeads. Mørch YA, Qi M, Gundersen PO, Formo K, Lacik I, Skjåk-Braek G, Oberholzer J, Strand BL. J Biomed Mater Res A. 2012 Nov;100(11):2939-47. doi: 10.1002/jbm.a.34237. Epub 2012 Jun 14. PubMed PMID: 22700168; PubMed Central PMCID: PMC3660841.

Survival of human islets in microbeads containing high guluronic acid alginate crosslinked with Ca2+ and Ba2+Qi M, Mørch Y, Lacík I, Formo K, Marchese E, Wang Y, Danielson KK, Kinzer K, Wang S, Barbaro B, Kolláriková G, Chorvát D Jr, Hunkeler D, Skjåk-Braek G, Oberholzer J, Strand BL. Xenotransplantation. 2012 Nov-Dec;19(6):355-64. doi: 10.1111/xen.12009. PubMed PMID: 23198731; PubMed Central PMCID: PMC3660848.

Effect of prolonged gelling time on the intrinsic properties of barium alginate microcapsules and its biocompatibility. Vaithilingam V, Kollarikova G, Qi M, Lacik I, Oberholzer J, Guillemin GJ, Tuch BE. J Microencapsul. 2011;28(6):499-507. doi: 10.3109/02652048.2011.586067. PubMed PMID: 21827357.

Encapsulation of human islets in novel inhomogeneous alginate-ca2+/ba2+ microbeads: in vitro and in vivo function. Qi M, Strand BL, Mørch Y, Lacík I, Wang Y, Salehi P, Barbaro B, Gangemi A, Kuechle J, Romagnoli T, Hansen MA, Rodriguez LA, Benedetti E, Hunkeler D, Skjåk-Braek G, Oberholzer J.  Artif Cells Blood Substit Immobil Biotechnol. 2008;36(5):403-20. doi: 10.1080/10731190802369755. PubMed PMID: 18925451; PubMed Central PMCID: PMC3748134.