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A new method for incorporating functional heparin onto the surface of islets of Langerhans
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
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2008 (English)In: Tissue Engineering. Part C, Methods, ISSN 1937-3384, Vol. 14, no 2, 141-147 p.Article in journal (Refereed) Published
Abstract [en]

A novel technique is described to conjugate macromolecular heparin complexes to cell surfaces. The method is based on the dual properties of avidin-expressing binding sites for both biotin and a macromolecular complex of heparin. A quartz crystal microbalance with dissipation monitoring (QCM-D) revealed sequential binding of biotin, avidin, and heparin complexes. Large particle flow cytometry confirmed functional integrity. Confocal microscopy of the heparinized islets showed evenly distributed fluorescence. An in vitro Chandler loop model demonstrated that the biocompatibility of the new method is comparable to the previous method used on artificial materials with regard to coagulation and antithrombin uptake. The technique presented allows human islets of Langerhans to successfully be covered with functional heparin as a means to reduce instant blood-mediated inflammatory reactions induced by the innate immune system.

Place, publisher, year, edition, pages
2008. Vol. 14, no 2, 141-147 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-96504DOI: 10.1089/ten.tec.2007.0312ISI: 000256675800005PubMedID: 18544029OAI: oai:DiVA.org:uu-96504DiVA: diva2:171101
Available from: 2007-11-15 Created: 2007-11-15 Last updated: 2009-11-02Bibliographically approved
In thesis
1. Pancreatic Islet Transplantation: Modifications of Islet Properties to Improve Graft Survival
Open this publication in new window or tab >>Pancreatic Islet Transplantation: Modifications of Islet Properties to Improve Graft Survival
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

During the past decade clinical islet transplantation has become a viable strategy for curing type 1 diabetes. The limited supply of organs, together with the requirement for islets from multiple donors to achieve insulin independence, has greatly limited the application of this approach.

The islets are infused into the liver via the portal vein, and once exposed to the blood, the grafted tissue has been shown to be damaged by the instant blood-mediated inflammatory reaction (IBMIR), which is characterized by coagulation and complement activation as well as leukocyte infiltration into the islets. Islet revascularization is a subsequent critical step for the long-term function of the transplanted graft, which may partially be impeded by the IBMIR.

In this thesis, we have explored novel strategies for circumventing the effects of the IBMIR and facilitating islet revascularization.

Systemic inhibitors of the IBMIR are typically associated with an increased risk of bleeding. We therefore evaluated alternative strategies for modulating the islets prior to transplantation. We demonstrated, using an adenoviral vector, that a high level of expression and secretion of the anticoagulant hirudin could be induced in human islets. An alternative approach to limiting the IBMIR was developed in which anticoagulant macromolecular heparin complexes were conjugated to the islet surface. This technique proved effective in limiting the IBMIR in both an in vitro blood loop model and an allogeneic porcine model of islet transplantation. An increased adhesion of endothelial cells to the heparin-coated islet surface was demonstrated, as was the capacity of the heparin conjugate to bind the angiogenic factors VEGF and FGF; these results have important implications for the revascularization process.

The outcome of the work in this thesis suggests that modulation of the islet surface is an attractive alternative to systemic therapy as a strategy for preventing the IBMIR. Moreover, the same techniques can be employed to induce revascularization and improve the engraftment of the transplanted islets. Ultimately, improved islet viability and engraftment will make islet transplantation a more effective procedure and increase the number of patients whose diabetes can be cured.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 60 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 297
Keyword
Medicine, Diabetes, islet transplantation, islets of Langerhans, coagulation activation, IBMIR, hirudin, heparin, growth factor, angiogenesis, Medicin
Identifiers
urn:nbn:se:uu:diva-8333 (URN)978-91-554-7039-5 (ISBN)
Public defence
2007-12-07, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjöldsväg 20, Uppsala, 09:15
Opponent
Supervisors
Available from: 2007-11-15 Created: 2007-11-15 Last updated: 2011-01-12Bibliographically approved

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