Biofabrication of a vascularized islet organ for type 1 diabetes

Antonio Citro, Philipp T. Moser, Erica Dugnani, Konrad T. Rajab, Xi Ren, Daniele Evangelista-Leite, Jonathan M. Charest, Andrea Peloso, Bruno K. Podesser, Fabio Manenti, Silvia Pellegrini, Lorenzo Piemonti, Harald C. Ott

Research output: Contribution to journalArticle

Abstract

Islet transplantation is superior to extrinsic insulin supplementation in the treating severe Type 1 diabetes. However, its efficiency and longevity are limited by substantial islet loss post-transplantation due to lack of engraftment and vascular supply. To overcome these limitations, we developed a novel approach to bio-fabricate functional, vascularized islet organs (VIOs) ex vivo. We endothelialized acellular lung matrixes to provide a biocompatible multicompartment scaffold with an intact hierarchical vascular tree as a backbone for islet engraftment. Over seven days of culture, islets anatomically and functionally integrated into the surrounding bio-engineered vasculature, generating a functional perfusable endocrine organ. When exposed to supra-physiologic arterial glucose levels in vivo and ex vivo, mature VIOs responded with a physiologic insulin release from the vein and provided more efficient reduction of hyperglycemia compared to intraportally transplanted fresh islets. In long-term transplants in diabetic mice, subcutaneously implanted VIOs achieved normoglycemia significantly faster and more efficiently compared to islets that were transplanted in deviceless fashion. We conclude that ex vivo bio-fabrication of VIOs enables islet engraftment and vascularization before transplantation, and thereby helps to overcome limited islet survival and function observed in conventional islet transplantation. Given recent progress in stem cells, this technology may enable assembly of functional personalized endocrine organs.

Original languageEnglish
Pages (from-to)40-51
Number of pages12
JournalBiomaterials
Volume199
DOIs
Publication statusPublished - Apr 1 2019

Fingerprint

Islets of Langerhans Transplantation
Insulin
Medical problems
Type 1 Diabetes Mellitus
Blood Vessels
Transplantation
Transplants
Stem cells
Scaffolds
Hyperglycemia
Glucose
Veins
Stem Cells
Technology
Fabrication
Lung

Keywords

  • Alternative site
  • Decellularization
  • Extracellular matrix
  • Islet transplantation
  • Lung scaffold
  • Tissue engineering
  • Type 1 diabetes

ASJC Scopus subject areas

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

Cite this

Citro, A., Moser, P. T., Dugnani, E., Rajab, K. T., Ren, X., Evangelista-Leite, D., ... Ott, H. C. (2019). Biofabrication of a vascularized islet organ for type 1 diabetes. Biomaterials, 199, 40-51. https://doi.org/10.1016/j.biomaterials.2019.01.035

Biofabrication of a vascularized islet organ for type 1 diabetes. / Citro, Antonio; Moser, Philipp T.; Dugnani, Erica; Rajab, Konrad T.; Ren, Xi; Evangelista-Leite, Daniele; Charest, Jonathan M.; Peloso, Andrea; Podesser, Bruno K.; Manenti, Fabio; Pellegrini, Silvia; Piemonti, Lorenzo; Ott, Harald C.

In: Biomaterials, Vol. 199, 01.04.2019, p. 40-51.

Research output: Contribution to journalArticle

Citro, A, Moser, PT, Dugnani, E, Rajab, KT, Ren, X, Evangelista-Leite, D, Charest, JM, Peloso, A, Podesser, BK, Manenti, F, Pellegrini, S, Piemonti, L & Ott, HC 2019, 'Biofabrication of a vascularized islet organ for type 1 diabetes', Biomaterials, vol. 199, pp. 40-51. https://doi.org/10.1016/j.biomaterials.2019.01.035
Citro, Antonio ; Moser, Philipp T. ; Dugnani, Erica ; Rajab, Konrad T. ; Ren, Xi ; Evangelista-Leite, Daniele ; Charest, Jonathan M. ; Peloso, Andrea ; Podesser, Bruno K. ; Manenti, Fabio ; Pellegrini, Silvia ; Piemonti, Lorenzo ; Ott, Harald C. / Biofabrication of a vascularized islet organ for type 1 diabetes. In: Biomaterials. 2019 ; Vol. 199. pp. 40-51.
@article{406c0bb0dc7e43248732a7b590744a72,
title = "Biofabrication of a vascularized islet organ for type 1 diabetes",
abstract = "Islet transplantation is superior to extrinsic insulin supplementation in the treating severe Type 1 diabetes. However, its efficiency and longevity are limited by substantial islet loss post-transplantation due to lack of engraftment and vascular supply. To overcome these limitations, we developed a novel approach to bio-fabricate functional, vascularized islet organs (VIOs) ex vivo. We endothelialized acellular lung matrixes to provide a biocompatible multicompartment scaffold with an intact hierarchical vascular tree as a backbone for islet engraftment. Over seven days of culture, islets anatomically and functionally integrated into the surrounding bio-engineered vasculature, generating a functional perfusable endocrine organ. When exposed to supra-physiologic arterial glucose levels in vivo and ex vivo, mature VIOs responded with a physiologic insulin release from the vein and provided more efficient reduction of hyperglycemia compared to intraportally transplanted fresh islets. In long-term transplants in diabetic mice, subcutaneously implanted VIOs achieved normoglycemia significantly faster and more efficiently compared to islets that were transplanted in deviceless fashion. We conclude that ex vivo bio-fabrication of VIOs enables islet engraftment and vascularization before transplantation, and thereby helps to overcome limited islet survival and function observed in conventional islet transplantation. Given recent progress in stem cells, this technology may enable assembly of functional personalized endocrine organs.",
keywords = "Alternative site, Decellularization, Extracellular matrix, Islet transplantation, Lung scaffold, Tissue engineering, Type 1 diabetes",
author = "Antonio Citro and Moser, {Philipp T.} and Erica Dugnani and Rajab, {Konrad T.} and Xi Ren and Daniele Evangelista-Leite and Charest, {Jonathan M.} and Andrea Peloso and Podesser, {Bruno K.} and Fabio Manenti and Silvia Pellegrini and Lorenzo Piemonti and Ott, {Harald C.}",
year = "2019",
month = "4",
day = "1",
doi = "10.1016/j.biomaterials.2019.01.035",
language = "English",
volume = "199",
pages = "40--51",
journal = "Biomaterials",
issn = "0142-9612",
publisher = "Elsevier BV",

}

TY - JOUR

T1 - Biofabrication of a vascularized islet organ for type 1 diabetes

AU - Citro, Antonio

AU - Moser, Philipp T.

AU - Dugnani, Erica

AU - Rajab, Konrad T.

AU - Ren, Xi

AU - Evangelista-Leite, Daniele

AU - Charest, Jonathan M.

AU - Peloso, Andrea

AU - Podesser, Bruno K.

AU - Manenti, Fabio

AU - Pellegrini, Silvia

AU - Piemonti, Lorenzo

AU - Ott, Harald C.

PY - 2019/4/1

Y1 - 2019/4/1

N2 - Islet transplantation is superior to extrinsic insulin supplementation in the treating severe Type 1 diabetes. However, its efficiency and longevity are limited by substantial islet loss post-transplantation due to lack of engraftment and vascular supply. To overcome these limitations, we developed a novel approach to bio-fabricate functional, vascularized islet organs (VIOs) ex vivo. We endothelialized acellular lung matrixes to provide a biocompatible multicompartment scaffold with an intact hierarchical vascular tree as a backbone for islet engraftment. Over seven days of culture, islets anatomically and functionally integrated into the surrounding bio-engineered vasculature, generating a functional perfusable endocrine organ. When exposed to supra-physiologic arterial glucose levels in vivo and ex vivo, mature VIOs responded with a physiologic insulin release from the vein and provided more efficient reduction of hyperglycemia compared to intraportally transplanted fresh islets. In long-term transplants in diabetic mice, subcutaneously implanted VIOs achieved normoglycemia significantly faster and more efficiently compared to islets that were transplanted in deviceless fashion. We conclude that ex vivo bio-fabrication of VIOs enables islet engraftment and vascularization before transplantation, and thereby helps to overcome limited islet survival and function observed in conventional islet transplantation. Given recent progress in stem cells, this technology may enable assembly of functional personalized endocrine organs.

AB - Islet transplantation is superior to extrinsic insulin supplementation in the treating severe Type 1 diabetes. However, its efficiency and longevity are limited by substantial islet loss post-transplantation due to lack of engraftment and vascular supply. To overcome these limitations, we developed a novel approach to bio-fabricate functional, vascularized islet organs (VIOs) ex vivo. We endothelialized acellular lung matrixes to provide a biocompatible multicompartment scaffold with an intact hierarchical vascular tree as a backbone for islet engraftment. Over seven days of culture, islets anatomically and functionally integrated into the surrounding bio-engineered vasculature, generating a functional perfusable endocrine organ. When exposed to supra-physiologic arterial glucose levels in vivo and ex vivo, mature VIOs responded with a physiologic insulin release from the vein and provided more efficient reduction of hyperglycemia compared to intraportally transplanted fresh islets. In long-term transplants in diabetic mice, subcutaneously implanted VIOs achieved normoglycemia significantly faster and more efficiently compared to islets that were transplanted in deviceless fashion. We conclude that ex vivo bio-fabrication of VIOs enables islet engraftment and vascularization before transplantation, and thereby helps to overcome limited islet survival and function observed in conventional islet transplantation. Given recent progress in stem cells, this technology may enable assembly of functional personalized endocrine organs.

KW - Alternative site

KW - Decellularization

KW - Extracellular matrix

KW - Islet transplantation

KW - Lung scaffold

KW - Tissue engineering

KW - Type 1 diabetes

UR - http://www.scopus.com/inward/record.url?scp=85061004780&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85061004780&partnerID=8YFLogxK

U2 - 10.1016/j.biomaterials.2019.01.035

DO - 10.1016/j.biomaterials.2019.01.035

M3 - Article

AN - SCOPUS:85061004780

VL - 199

SP - 40

EP - 51

JO - Biomaterials

JF - Biomaterials

SN - 0142-9612

ER -