Abstract
Increasing individuals diagnosed with type II diabetes pose a strong demand for the development of more effective anti-diabetic drugs. However, expensive, ethically controversial animal-based screening for anti-diabetic compounds is not always predictive of the human response. The use of in vitro cell-based models in research presents obviously ethical and cost advantages over in vivo models. This study was to develop an in vitro three-dimensional (3D) perfused culture model of islets (Islet TF) for maintaining viability and functionality longer for diabetic drug efficacy tests. Briefly fresh isolated rat islets were encapsulated in ultrapure alginate and the encapsulated islets were cultured in TissueFlex®, a multiple, parallel perfused microbioreactor system for 7 days. The encapsulated islets cultured statically in cell culture plates (3D static) and islets cultured in suspension (2D) were used as the comparisons. In this study we demonstrate for the first time that Islet TF model can maintain the in vitro islet viability, and more importantly, the elevated functionality in terms of insulin release and dynamic responses over a 7-day culture period. The Islet TF displays a high sensitivity in responding to drugs and drug dosages over conventional 2D and 3D static models. Actual drug administration in clinics could be simulated using the developed Islet TF model, and the patterns of insulin release response to the tested drugs were in agreement with the data obtained in vivo. Islet TF could be a more predictive in vitro model for routine short- and long-term anti-diabetic drug efficacy testing.
Highlights
The number of individuals diagnosed with type II diabetes, which is caused by the ‘metabolic syndrome’ – obesity, insulin resistance and/or abnormal insulin secretion, is increasing worldwide, and creating a strong demand for the development of more effective anti-diabetic drugs [1]
The functional marker, insulin release response to serial concentrations of glucose, was determined using a commercial ELISA kit to evaluate the key function of islet retained during the culture period
Fluorescent images demonstrated that rat islets cultured in 3D alginate beads under both static and perfusion culture conditions maintained their intact body shape and viability in 7-day culture (Figure 1 C, D, E & F)
Summary
The number of individuals diagnosed with type II diabetes, which is caused by the ‘metabolic syndrome’ – obesity, insulin resistance and/or abnormal insulin secretion, is increasing worldwide, and creating a strong demand for the development of more effective anti-diabetic drugs [1]. The use of in vitro cell-based models in research presents obviously ethical and cost advantages over in vivo models. In vitro research has been conducted using 2D cell cultures. Conventional 2D cell culture where cells are cultured on flat, rigid plastic substrates does not reproduce the tissue architecture in vivo, and do not forecast organ-specific toxicity [4,5]. This is because real tissues have a 3D geometry, gel-like stiffness, and complex organisation of extracellular matrix (ECM). This is because real tissues have a 3D geometry, gel-like stiffness, and complex organisation of extracellular matrix (ECM). 3D cell cultures establish cell-cell contacts and cell-ECM interactions by embedding cells in 3D scaffolds that mimics the biochemistry and mechanics of the microenvironment in vivo, offers a practical alternative to natural tissue models
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