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Animal-free diabetes research with the pancreas chip

Quite a number of promising drug candidates for the treatment of diabetes are currently in the pharmaceutical pipeline, including innovative drugs that can stimulate the regeneration of insulin-producing pancreatic cells. However, they will have to be safety tested in animals as a reliable and regulatory accepted animal-free method does not yet exist. Scientists from Ulm University Hospital have now begun to develop a pancreatic chip from stem cells which the pharmaceutical industry could, in future, use for the high-throughput testing of a large number of active pharmaceutical ingredients.

A team of researchers led by Prof. Alexander Kleger (top row, 3rd from the left) at Ulm University Hospital is involved in the PancChip project, which is aimed at the development of an in vitro pancreas model to improve research and the development of new drugs for the treatment of pancreatic disorders. © Sandra Heller, Ulm University Hospital

Diabetes mellitus refers to a number of metabolic disorders such as type 1 which results from the complete or partial destruction of the insulin-producing beta cells of the pancreas through the body’s immune system, and type 2 in which cells are unable to use insulin effectively through acquired insulin resistance. As a result, the body fails to adequately regulate the blood sugar levels. Standard treatment of diabetes mellitus involves the injection of man-made insulin. A therapy that fights the actual cause of diabetes mellitus is still elusive and one of the main reasons for this is the lack of a complex in-vitro model that mirrors the organ and its interactions in the body as realistically as possible. With such a model it would be possible to study the development of diabetes in greater detail as well as advance the development of effective drugs. Such models could also be applied to other pancreatic disorders.

A project to change the current situation was therefore initiated in the Department of Internal Medicine I at Ulm University Hospital by a group of researchers led by Prof. Dr. rer. med. Alexander Kleger. Kleger’s group is part of the PancChip consortium which also includes scientists led by Dr. med. Matthias Meier from the Department of Microsystems Technology (IMTEK) at the University of Freiburg and scientists led by Prof. Dr. med. Heiko Lickert from the Institute of Diabetes and Regeneration Research (IDR) at the Helmholtz Zentrum München, the German Research Centre for Environmental Health. Coordinated by Prof. Lickert, the objective of the PancChip consortium is to further develop the culture and differentiation of stem cells into functional beta cells on a microfluidic chip. The goal is to use this pancreatic chip as a patient-specific model for investigating the development and treatment of diabetes, pancreatitis and pancreatic cancer. The project is funded by the German Federal Ministry of Education and Research (BMBF) and will run for three years.

Results from animal experiments can, in many cases, not be transferred to the situation in humans

Dr. Sandra Heller from Ulm University Hospital is involved in research into novel diabetes drugs and was recently awarded the Lush Prize 2017 for her achievements in the field of animal-free research methods. © Sandra Heller, Ulm University Hospital

Dr. Sandra Heller, a biologist from the University of Ulm, is in charge of the experimental work involving stem cell cultures. Animal welfare is particularly important to her and she has therefore been studying animal-free testing methods for quite some time. She was recently awarded the Lush Prize 2017 in the category “Young Researcher” for her work in this field. The Lush Prize funds methods that have the aim of replacing the use of animals in the testing of medical products. “At present, diabetes drug candidates still have to be tested in animals. Cells that can be grown easily in the incubator are not suitable for such tests,” said Heller. “The problem is not only that animals are used for these types of tests. There is also the problem that animals are different from humans, so information obtained with animal tests cannot be extrapolated 100% to humans. We hope that we will soon be able to test drug candidates in human cell cultures under conditions that reflect the human system far better than animal systems can.” The researchers place particular hope on therapies that are able to regenerate or replace diseased pancreatic cells. They have therefore decided to use stem cells as sources of insulin-producing cells, in particular stem cells from healthy donors that have been reprogrammed into pluripotent stem cells. Patient cells are also used.

High-throughput miniaturised drug screening tests

Heller and her colleagues possess the expertise that is needed to generate such stem cells in the laboratory: "The system for producing insulin-producing cells is already available. Our task within the consortium is now to improve the maturation process of these cells for use in cell replacement therapy and also to grow cells on a larger scale," said Heller. "We will then be able to use them on the pancreas chip for the miniaturised, high-throughput testing of potential drugs. Our partners possess the knowledge needed to develop and manufacture the chip, the development of which is currently being concluded in parallel to our work with the cells.”

The tests for the regeneration of pancreatic cells will be carried out with what are known as stem cell micro-islets - small units with less than one hundred cells in a three-dimensional culture, which are invisible to the naked eye. In order to make such micro-islets, the stem cells are first treated with growth factors, which cause them to differentiate into the desired insulin-producing cells in a multi-step, optimised process. “Then we have to apply a special technique which involves counting the cells and letting them aggregate once again in the culture dishes so that they form small clumps, the micro-islets.”

Personalised tests for diabetes patients

Hair roots from diabetes patients at Ulm University Hospital are also used to generate reprogrammed stem cells. This enables the researchers to perform personalised drug screening. © Sandra Heller, Ulm University Hospital

The researchers use reprogrammed pluripotent stem cell lines and stem cells from patients at Ulm University Hospital to produce cells for research purposes: “At the hospital, we have a database in which information about patients with a genetic pancreas defect is stored. Here, we can also get samples of hair from the patients,” said Heller. “The use of sample material for research purposes was reviewed and approved by the ethics committee and is also subject to patient consent. The technique involves simply plucking ten to twenty hairs from the scalp of the patient. This is not particularly painful and does not have to be done by a medical doctor. The hair root cells are then grown in cell culture. From these cells we can obtain patient-specific pluripotent cells. So far, we have around 15 patient-specific cell lines.” As the cells come directly from patients, they have the potential of being used for personalised drug screening tests for diabetics.

Outlook: pancreas chips that work like a printer

The idea for future drug tests is to further develop the current chip versions into micro-islet-secretion-print-chips (MISP-chips) that enable the parallel testing of several active ingredients. The cells are contained in small vessels and incubated with substances of interest. “The basic system functions like a printer,” said Heller. “The medium that surrounds the cells is deposited on a membrane, where the result is visualised and analysed. This is achieved by coupling a specific antibody reaction with a polymerase chain reaction. The two individual methods are already well established, and will now be integrated into the MISP-chip system.”

Along with the other funds the consortium has received, the Lush Prize will be used to advance the project, i.e. to develop the chip platform towards market maturity. Heller commented: "A prototype chip exists already, but this has not yet been loaded with cells. Finding out how this can be done most effectively will take at least a year as work with stem cells is particularly difficult. It takes quite some time to develop a protocol, and, above all, a standardised one. We are exchanging information about problems and results with the other research groups involved in the consortium at regular intervals. This exchange has also led to the plan to not only load the chip with insulin-producing cells, but also with other pancreatic cells. In addition, the chip has also the potential to be used for completely different body cells. So our goal is to develop the platform as universal system.”

It is likely that the pharmaceutical industry will be able to use universal microfluidic chip systems that are combined with three-dimensional cell cultures to perform a variety of high-throughput drug tests. “However, no concrete plans for doing so are yet available as the results are still coming in,” explained Heller. “The consortium itself has also plans to use the chips for testing drugs. To achieve this, there is a plan to establish a start-up company with funds from the BMBF’s EXIST programme and/or the VIP+ funding programme.”

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