A novel approach to xenotransplantation combining surface engineering and genetic modification of isolated adult porcine islets

Contreras, Juan L.; Xie, Dong; Mays, Jimmy W.; Smyth, Cheryl A.; Eckstein, Christopher; Rahemtulla, Firoz; Young, Carlton J.; Thompson, John A.; Bilbao, Guadalupe; Curiel, David T.; Eckhoff, Devin E.

doi:10.1016/j.surg.2004.05.031

Cited by 77 publications

(66 citation statements)

References 25 publications

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“…Several groups have demonstrated that immobilization of PEG chains to the islet surface provides a mechanism of preventing, or at least attenuating host response to both allo- [56][57][58][59][60] and xenografts. 61,62 For example, covalent coupling of PEG to amines of cell surface proteins or carbohydrates, or by direct insertion of PEG-lipid into the cell membrane through hydrophobic interaction has been applied to form a thin polymer layer on islet surfaces to provide immunoisolation. It was also reported that graft survival can be improved by immobilizing heparin or thrombomodulin to the islet surface to inhibit blood coagu-…”

Section: Figmentioning

confidence: 99%

Encapsulation of Pancreatic Islets Within Nano-Thin Functional Polyethylene Glycol Coatings for Enhanced Insulin Secretion

Kızılel

Scavone

Liu

et al. 2010

Tissue Engineering Part A

103

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Covalent attachment of polymers to cells and tissues could be used to solve a variety of problems associated with cellular therapies. Insulin-dependent diabetes mellitus is a disease resulting from the autoimmune destruction of the b cells of the islets of Langerhans in the pancreas. Transplantation of islets into diabetic patients is an attractive form of treatment, provided that the islets could be protected from the host's immune system to prevent graft rejection, and smaller numbers of islets transplanted in smaller volumes could be sufficient to reverse diabetes. Therefore, a need exists to develop islet encapsulation strategies that minimize transplant volume. In this study, we demonstrate the formation of nano-thin, poly(ethylene glycol) (PEG)-rich functional conformal coatings on individual islets via layer-by-layer assembly technique. The surface of the islets is modified with biotin-PEG-N-hydroxysuccinimide (NHS), and the islets are further covered by streptavidin (SA) and biotin-PEG-peptide conjugates using the layer-by-layer method. An insulinotropic ligand, glucagon-like peptide-1 (GLP-1), is conjugated to biotin-PEG-NHS. The insulinotropic effect of GLP-1 is investigated through layer-by-layer encapsulation of islets using the biotin-PEG-GLP-1 conjugate. The effect of islet surface modification using the biotin-PEG-GLP-1 conjugate on insulin secretion in response to glucose challenge is compared via static incubation and dynamic perifusion assays. The results show that islets coated with the functional PEG conjugate are capable of secreting more insulin in response to high glucose levels compared to control islets. Finally, the presence of SA is confirmed by indirect fluorescent staining with SA-Cy3, and the presence of PEGpeptide on the surface of the islets after treatment with biotin-PEG-GLP-1 is confirmed by indirect fluorescent staining with biotin-PEG-fluorescein isothiocyanate (FITC) and separately with an anti-GLP-1 antibody. This work demonstrates the feasibility of treating pancreatic islets with reactive polymeric segments and provides the foundation for a novel means of potential immunoisolation. With this technique, it may be possible to encapsulate and/or modify islets before portal vein transplantation and reduce transplantation volume significantly, and promote islet viability and insulin secretion due to the presence of insulinotropic peptides on the islet surface. Layer-by-layer self-assembly of PEG-GLP-1 offers a unique approach to islet encapsulation to stimulate insulin secretion in response to high glucose levels.

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Section: Figmentioning

confidence: 99%

Encapsulation of Pancreatic Islets Within Nano-Thin Functional Polyethylene Glycol Coatings for Enhanced Insulin Secretion

Kızılel

Scavone

Liu

et al. 2010

Tissue Engineering Part A

103

View full text Add to dashboard Cite

show abstract

“…To address multipronged mechanisms of islet destruction, Contreras et al (2004b) evaluated xenotransplantation of porcine islets in NOD-SCID mice after genetic modification of islets with the antiapoptotic gene Bcl-2 and cell surface modification with PEG derivatives. This two-pronged approach promised to block host antibody binding to graft surface antigens due to hydrophilic PEG surface coating, while promising the cytoprotective effects of Bcl-2 gene expression in the islets as demonstrated earlier .…”

Section: Approaches For Improving Islet Transplantationmentioning

confidence: 99%

Biological and Biomaterial Approaches for Improved Islet Transplantation

2006

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“…The genetic modification of islet cells is also a practical method for generating new transplantable grafts with special resistances. For example, the immunoisolation of APIs genetically modified to overexpress antiapoptotic Bcl-2 gene could significantly reduce islet loss after intraportal infusion (Contreras et al, 2004). The successful application of combined encapsulation and genetic modification technologies opens up a new strategy to improve the outcomes from xenoislet transplantation.…”

Section: Sources Of Pig Isletsmentioning

confidence: 99%

“…Islet surface modification with the biologically inert, amphiphilic polymer polyethylene glycol (PEG) has emerged as a promising and alternative approach. Not only did PEGylation have no adverse effects on islet morphology, viability, or functionality (Cruise et al, 1998;Contreras et al, 2004;Teramura and Iwata, 2009), but it was also found to prevent islet recognition by activated immune cells in vitro (Lee et al, 2004) and to reduce islet allograft damage or loss after intraportal transplantation (Teramura and Iwata, 2009). However, some in vivo studies suggested that islet surface modification alone, either with a PEG or heparin coating, was not a very stable immunoprotective method since combinatory treatments of lowdose immunosuppressants (e.g.…”

Section: Future Directions: Conformal Coatingmentioning

confidence: 99%

Treatment of diabetes with encapsulated pig islets: an update on current developments

Zhu

Liu

et al. 2015

J. Zhejiang Univ. Sci. B

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Abstract:The potential use of allogeneic islet transplantation in curing type 1 diabetes mellitus has been adequately demonstrated, but its large-scale application is limited by the short supply of donor islets and the need for sustained and heavy immunosuppressive therapy. Encapsulation of pig islets was therefore suggested with a view to providing a possible alternative source of islet grafts and avoiding chronic immunosuppression and associated adverse or toxic effects. Nevertheless, several vital elements should be taken into account before this therapy becomes a clinical reality, including cell sources, encapsulation approaches, and implantation sites. This paper provides a comprehensive review of xenotransplantation of encapsulated pig islets for the treatment of type 1 diabetes mellitus, including current research findings and suggestions for future studies.

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A novel approach to xenotransplantation combining surface engineering and genetic modification of isolated adult porcine islets

Cited by 77 publications

References 25 publications

Encapsulation of Pancreatic Islets Within Nano-Thin Functional Polyethylene Glycol Coatings for Enhanced Insulin Secretion

Encapsulation of Pancreatic Islets Within Nano-Thin Functional Polyethylene Glycol Coatings for Enhanced Insulin Secretion

Biological and Biomaterial Approaches for Improved Islet Transplantation

Treatment of diabetes with encapsulated pig islets: an update on current developments

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