Endothelialized collagen based pseudo-islets enables tuneable subcutaneous diabetes therapy

Vlahos, Alexander E.; Kinney, Sean M.; Kingston, Benjamin R.; Keshavjee, S.; Won, So-Yoon; Martyts, Anastasiya; Chan, Warren C. W.; Sefton, Michael V.

doi:10.1016/j.biomaterials.2019.119710

Cited by 44 publications

(44 citation statements)

References 49 publications

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“…The native pancreatic islets range is from 50 to 400 mm in diameter with an average size of 150 mm. 20,21 Therefore, pseudoislets were formed by spontaneous aggregation with 500 to 10,000 cells per pseudoislets (Fig. 1).…”

Section: Assembly Of Pancreatic B-cells Into Glucose-responsive Pseudmentioning

confidence: 99%

Collagen and Endothelial Cell Coculture Improves β-Cell Functionality and Rescues Pancreatic Extracellular Matrix

Zbinden

Urbanczyk

Layland

et al. 2021

Tissue Engineering Part A

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The use of biomaterials and biomaterial functionalization is a promising approach to support pancreatic islet viability posttransplantation in an effort to reduce insulin dependence for patients afflicted with diabetes mellitus type 1. Extracellular matrix (ECM) proteins are known to impact numerous reparative functions in the body. Assessing how endogenously expressed pancreatic ECM proteins are affected by posttransplant-like hypoxic conditions may provide significant insights toward the development of tissue-engineered therapeutic strategies to positively influence b-cell survival, proliferation, and functionality. Here, we investigated the expression of three relevant groups of pancreatic ECM proteins in human native tissue, including basement membrane (BM) proteins (collagen type 4 [COL4], laminins [LAM]), proteoglycans (decorin [DCN], nidogen-1 [NID1]), and fibril-forming proteins (fibronectin [FN], collagen type 1 [COL1]). In an in vitro hypoxia model, we identified that ECM proteins were differently affected by hypoxic conditions, contributing to an overall loss of b-cell functionality. The use of a COL1 hydrogel as carrier material demonstrated a protective effect on bcells mitigating the effect of hypoxia on proteoglycans as well as fibril-forming protein expression, supporting b-cell functionality in hypoxia. We further showed that providing endothelial cells (ECs) into the COL1 hydrogel improves b-cell response as well as the expression of relevant BM proteins. Our data show that b-cells benefit from a microenvironment composed of structure-providing COL1 with the incorporation of ECs to withstand the harsh conditions of hypoxia. Such hydrogels support b-cell survival and can serve as an initial source of ECM proteins to allow cell engraftment while preserving cell functionality posttransplantation.

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Section: Assembly Of Pancreatic B-cells Into Glucose-responsive Pseudmentioning

confidence: 99%

Collagen and Endothelial Cell Coculture Improves β-Cell Functionality and Rescues Pancreatic Extracellular Matrix

Zbinden

Urbanczyk

Layland

et al. 2021

Tissue Engineering Part A

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“…However, the subcutaneous site is poorly vascularized and must be modified to support the engraftment of pancreatic islets. There have been various successful approaches for subcutaneously delivering pancreatic islets, such as delivering them within biomaterials 3 , with cells 1,4 , or in large macro devices 5,6 . These approaches all support islet engraftment; however, many require an excess of islets to achieve normoglycemia.…”

Section: -Introductionmentioning

confidence: 99%

A scalable device-less biomaterial approach for subcutaneous islet transplantation

et al. 2021

Self Cite

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In this study methacrylic acid copolymer coated tubes generated a robust vascular response in the subcutaneous space, which was critical to support islet transplantation in a streptozotocin-induced diabetic mouse model. More importantly, the subcutaneous prevascularization approach using this copolymer coating was scalable into a larger allogeneic rat model and returned animals to normoglycemia for up to 70 days. This platform highlights the potential of a scalable biomaterial approach for pre-vascularization of the subcutaneous space in larger animal models.

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“…The present study evaluated a 5 mm-long cylindrical silicone chamber filled with Matrigel™ matrix placed in the groins of mice surrounding the superficial epigastric vessel. Matrigel™ originated from the Engelbreth-Holm-Swarm mouse sarcoma and was found to be a substrate that induces angiogenesis in vivo [27]. In particular, major components, including laminin and collagen IV, modulate cell signaling interactions and are critical for pancreatic βcell survival and differentiation [28].…”

Section: Discussionmentioning

confidence: 99%

A novel prevascularized tissue-engineered chamber as a site for allogeneic and xenogeneic islet transplantation to establish a bioartificial pancreas

et al. 2020

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Although sites for clinical or experimental islet transplantation are well established, pancreatic islet survival and function in these locations remain unsatisfactory. A possible factor that might account for this outcome is local hypoxia caused by the limited blood supply. Here, we modified a prevascularized tissue-engineered chamber (TEC) that facilitated the viability and function of the seeded islets in vivo by providing a microvascular network prior to transplantation. TECs were created, filled with Growth Factor-Matrigel™ (Matrigel™) and then implanted into the groins of mice with streptozotocin-induced diabetes. The degree of microvascularization in each TECs was analyzed by histology, real-time PCR, and Western blotting. Three hundred syngeneic islets were seeded into each chamber on days 0, 14, and 28 post-chamber implantation, and 300, 200, or 100 syngeneic islets were seeded into additional chambers on day 28 post-implantation, respectively. Furthermore, allogeneic or xenogeneic islet transplantation is a potential solution for organ shortage. The feasibility of TECs as transplantation sites for islet allografts or xenografts and treatment with anti-CD45RB and/or anti-CD40L (MR-1) was therefore explored. A highly developed microvascularized network was established in each TEC on day 28 post-implantation. Normalization of blood glucose levels in diabetic mice was negatively correlated with the duration of prevascularization and the number of seeded syngeneic islets. Combined treatment with anti-CD45RB and MR-1 resulted in long-term survival of the grafts following allotransplantation (5/5, 100%) and xenotransplantation (16/20, 80%). Flow cytometry demonstrated that the frequency of CD4+Foxp3-Treg and CD4+IL-4+-Th2 cells increased significantly after tolerogenic xenograft transplantation, while the number of CD4+IFN-γ-Th1 cells decreased. These findings demonstrate that highly developed microvascularized constructs can facilitate the survival of transplanted islets in a TECs, implying its potential application as artificial pancreas in the future.

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Endothelialized collagen based pseudo-islets enables tuneable subcutaneous diabetes therapy

Cited by 44 publications

References 49 publications

Collagen and Endothelial Cell Coculture Improves β-Cell Functionality and Rescues Pancreatic Extracellular Matrix

Collagen and Endothelial Cell Coculture Improves β-Cell Functionality and Rescues Pancreatic Extracellular Matrix

A scalable device-less biomaterial approach for subcutaneous islet transplantation

A novel prevascularized tissue-engineered chamber as a site for allogeneic and xenogeneic islet transplantation to establish a bioartificial pancreas

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