Microwell Scaffolds Using Collagen-IV and Laminin-111 Lead to Improved Insulin Secretion of Human Islets

Abstract

Intrahepatic islet transplantation is a promising therapy for treatment of type 1 diabetes. During islet isolation, collagenase is used to extract islets from the pancreas, leading to loss of important cell–matrix interactions. Loss of the native pancreatic microenvironment is associated with apoptosis of islet cells, early graft failure, and poor islet function. The islet extracellular matrix (ECM) is composed of a specific combination of collagen (Col), laminin (LN), and fibronectin (FN) molecules. Reintroducing these molecules has been shown to boost the function, viability, morphology, and proliferation of β-cells. In this research, the effect of combinatorial ECM on islet function and survival was investigated. Specifically, thin-film microwell array scaffolds made from two distinct biomaterials were coated with FN, collagen type IV (Col4), LN111, LN332, or a combination thereof. We found that coatings containing a single type of ECM molecule, for example, FN or Col, can improve short-term islet function. However, these single proteins do not prevent loss of morphology and subsequent loss of islet function afterward. In contrast, combining Col4 with LN111 at a ratio of 8:2 not only improved short-term islet function but also preserved islet structure and islet function on a longer term. This effect was reproducibly shown on poly(ester-urethane) and poly(ethylene-glycol-terephthalate-poly(butylene-terephthalate) microwell islet delivery devices as well as tissue culture polystyrene. We concluded that biofunctionalization of inert biomaterials regardless of their molecular composition with a specific combination of islet ECM molecules can support and improve islet function over longer time periods. Our data suggested that creating a biomimetic islet niche by biofunctionalization of biomaterials can significantly improve the endocrine function of β-cells. The creation of islet mimicking niches in islet delivery devices leads to an improvement of islet function by restoring part of the islet's ECM in these devices.

Impact Statement

This research deals with finding a proper bioengineering strategy to improve the outcome of islets transplantation for treatment of type 1 diabetes. It is focused on the mimicking of islet extracellular matrix niche in microwell islet delivery devices to improve their endocrine function.