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... Show moreIntrahepatic 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 beta-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 beta-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. Show less
Although the extracellular matrix (ECM) is the key determinant of the mechanical behavior and stability of tissue, remarkably little is known on this tissue component. Most biomedical research on... Show moreAlthough the extracellular matrix (ECM) is the key determinant of the mechanical behavior and stability of tissue, remarkably little is known on this tissue component. Most biomedical research on the human aorta focuses on biochemical analysis of tissues or the properties of specific cells in the aorta. We show that a physics-based approach can yield important complementary insight. By measuring the mechanical response of the ECM by AFM and imaging it with multi-photon microscopy, we show that the spatial organization of the network structure of collagen fibers plays an important role. First we show how aneurysms, a local dilatation of the arterial wall, are caused by profound defects in collagen network. The collagen fibers in het healthy aorta are organized in a loose braiding of collagen ribbons, while the aneurysmatic tissue show dramatically altered collagen architectures with loss of the collagen knitting. Evaluation by AFM shows how this altered network could explain the failure of the tissue. In a follow-up study, we examine the effects of enzymatic digestion of the ECM of the aortic wall. By starting with real tissue and selectively removing different elements, we are able to measure the contribution of the different constituents of the ECM to the mechanical properties of the whole tissue. We also show how the content of neutrophils is able to mimic the observed change in mechanical response from a healthy aorta to an aneurysm. Finally we will show first results on the disease of atherosclerosis, another common vascular disease. The collagen structure of the cap changes during the growth of the atherosclerotic plaque and we discuss its mechanical implications. This study gives key insights in the failure mechanism of two common pathologies and provides biomedical researchers a new, physics-oriented view to organs, with implications for the study of wound healing, myocardial infarction and cancer cell migration. Show less
