Enhancing human islet transplantation by localized release of trophic factors from PLG scaffolds

K. A. Hlavaty, R. F. Gibly, X. Zhang, C. B. Rives, J. G. Graham, W. L. Lowe*, X. Luo, L. D. Shea

*Corresponding author for this work

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Islet transplantation represents a potential cure for type 1 diabetes, yet the clinical approach of intrahepatic delivery is limited by the microenvironment. Microporous scaffolds enable extrahepatic transplantation, and the microenvironment can be designed to enhance islet engraftment and function. We investigated localized trophic factor delivery in a xenogeneic human islet to mouse model of islet transplantation. Double emulsion microspheres containing exendin-4 (Ex4) or insulin-like growth factor-1 (IGF-1) were incorporated into a layered scaffold design consisting of porous outer layers for islet transplantation and a center layer for sustained factor release. Protein encapsulation and release were dependent on both the polymer concentration and the identity of the protein. Proteins retained bioactivity upon release from scaffolds in vitro. A minimal human islet mass transplanted on Ex4-releasing scaffolds demonstrated significant improvement and prolongation of graft function relative to blank scaffolds carrying no protein, and the release profile significantly impacted the duration over which the graft functioned. Ex4-releasing scaffolds enabled better glycemic control in animals subjected to an intraperitoneal glucose tolerance test. Scaffolds releasing IGF-1 lowered blood glucose levels, yet the reduction was insufficient to achieve euglycemia. Ex4-delivering scaffolds provide an extrahepatic transplantation site for modulating the islet microenvironment to enhance islet function posttransplant. This study investigates localized trophic factor delivery from biomaterial scaffolds in a xenogeneic human islet to mouse model of islet transplantation, and demonstrates that Exendin-4 releasing scaffolds significantly enhance islet engraftment and prolong graft function with transplantation of a minimal mass of human islets.

Original languageEnglish (US)
Pages (from-to)1523-1532
Number of pages10
JournalAmerican Journal of Transplantation
Volume14
Issue number7
DOIs
StatePublished - Jul 2014

Fingerprint

Islets of Langerhans Transplantation
Transplantation
Somatomedins
Transplants
Proteins
Biocompatible Materials
Glucose Tolerance Test
Emulsions
Type 1 Diabetes Mellitus
Microspheres
Blood Glucose
Polymers
exenatide

Keywords

  • Bioengineering
  • islet xenotransplantation
  • regenerative medicine
  • type 1 diabetes mellitus

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

Cite this

Hlavaty, K. A. ; Gibly, R. F. ; Zhang, X. ; Rives, C. B. ; Graham, J. G. ; Lowe, W. L. ; Luo, X. ; Shea, L. D. / Enhancing human islet transplantation by localized release of trophic factors from PLG scaffolds. In: American Journal of Transplantation. 2014 ; Vol. 14, No. 7. pp. 1523-1532.
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abstract = "Islet transplantation represents a potential cure for type 1 diabetes, yet the clinical approach of intrahepatic delivery is limited by the microenvironment. Microporous scaffolds enable extrahepatic transplantation, and the microenvironment can be designed to enhance islet engraftment and function. We investigated localized trophic factor delivery in a xenogeneic human islet to mouse model of islet transplantation. Double emulsion microspheres containing exendin-4 (Ex4) or insulin-like growth factor-1 (IGF-1) were incorporated into a layered scaffold design consisting of porous outer layers for islet transplantation and a center layer for sustained factor release. Protein encapsulation and release were dependent on both the polymer concentration and the identity of the protein. Proteins retained bioactivity upon release from scaffolds in vitro. A minimal human islet mass transplanted on Ex4-releasing scaffolds demonstrated significant improvement and prolongation of graft function relative to blank scaffolds carrying no protein, and the release profile significantly impacted the duration over which the graft functioned. Ex4-releasing scaffolds enabled better glycemic control in animals subjected to an intraperitoneal glucose tolerance test. Scaffolds releasing IGF-1 lowered blood glucose levels, yet the reduction was insufficient to achieve euglycemia. Ex4-delivering scaffolds provide an extrahepatic transplantation site for modulating the islet microenvironment to enhance islet function posttransplant. This study investigates localized trophic factor delivery from biomaterial scaffolds in a xenogeneic human islet to mouse model of islet transplantation, and demonstrates that Exendin-4 releasing scaffolds significantly enhance islet engraftment and prolong graft function with transplantation of a minimal mass of human islets.",
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Enhancing human islet transplantation by localized release of trophic factors from PLG scaffolds. / Hlavaty, K. A.; Gibly, R. F.; Zhang, X.; Rives, C. B.; Graham, J. G.; Lowe, W. L.; Luo, X.; Shea, L. D.

In: American Journal of Transplantation, Vol. 14, No. 7, 07.2014, p. 1523-1532.

Research output: Contribution to journalArticle

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AU - Gibly, R. F.

AU - Zhang, X.

AU - Rives, C. B.

AU - Graham, J. G.

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AU - Shea, L. D.

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