Developing a human vascularised pancreatic islet on a chip - VIOC

Maintaining blood sugar levels within a remarkably narrow range despite large variations in how much we eat or exercise is one of the marvels of the human body. Two hormones each with opposing effects, glucagon and insulin, are the main regulators of blood sugar. They are released from tiny "islets" that are dispersed throughout the pancreas. Islet cells constantly sense sugar levels in the blood and respond in a finely tuned manner to release the right mix of insulin and glucagon to tightly control our blood sugar levels. There remain fundamental gaps in our understanding of how islets work in healthy people to regulate blood sugar. Furthermore, discovering how to restore these mechanisms in patients with diabetes, now affecting over 1 in 11 adults, is essential if we are to find a cure for the disease.

We have recently shown that the hormone secreting cells within the islets are connected and communication between them is essential for orchestrating healthy insulin release. To date most of our understanding about islet function comes from rodent studies, since human islets are too small to radiologically image and the pancreas is too deep and dangerous to biopsy. However, the relative positions of the different hormone-secreting cell types differs quite markedly between human and rodent islets and the blood circulation is different too. This limits our ability to make conclusions about human islet function from rodent studies. Some labs are able to perform experiments on islets donated to medical research by people who have died. However, in a petri dish with culture medium these precious islets quickly die. We are unable re-create the important element of blood flow through capillaries within the islet that carry in nutrients (like sugar) and pass on important hormonal messages within the islet itself and beyond.

Therefore the aim of this project is to extend the life and utility of donor human islets in a device that supports the islets to become embedded and ultimately vascularised in a bed of human capillaries. This "vascularised islet on a chip" or VIOC will allow us to circulate nutrients through the blood vessel network and through the islet, keeping it alive for much longer than is now possible. The chip will be transparent so that we can examine the responses of human islets under the microscope in real-time and it can also be linked to hormone measuring devices to achieve readouts of hormone secretory function. VIOC will allow us to study human islet function in response to a range of experiments that could help us answer fundamental questions that are still unknown - for example whether specific nutrients (breakdown products of fat or protein metabolism) have particular benefits on insulin secretion or how the immune system interacts with islets to protect them from damage. We will work with our network of collaborators in the field of islet biology to validate VIOC as an effective and indeed superior replacement for rodents to interrogate islet function in health and disease.

Cadaveric human donor islets may be used to study insulin release in static culture medium, although with the best curation such islets last a few days before developing a necrotic core, and calcium responses to glucose stimuli decay after as little as 24 hours. A few islet-on-chip devices have been developed but still have significant design hurdles to overcome. Some utilise circulating systems around trapped islets to spectroscopically measure insulin release as a means of assaying viability prior to clinical transplant. Such designs are not intended for longer term, longitudinal studies. Others have attempted to vascularise islets on a chip to improve their longevity or to specifically study the interaction of the islet with its capillary bed. There is no published study that has proven islet intravasation or perfusion. The benefits and uniqueness of our approach is that we will use vascular networks grown from blood outgrowth endothelial cells (BOECs), which are more relevant that umbilical vein derived endothelial cells to model the microenvironment of the mature adult islet. Furthermore we will use our existing expertise in sustaining large tissue explants using mass perfusion to prolong the viability of our human donor islets until they vascularise. Finally, we will utilise our engineering expertise to modify existing chip designs in order to allow us to integrate a fresh donor islet into a pre-existing vascular network, which we hypothesise will provide a time advantage to the process of intra-islet anastomoses and true vascular perfusion.
By the end of this project, we will have developed and validated a user-friendly device that could routinely be used to enhance longitudinal readouts from donated human islets thereby alleviating the need for donor rodent islets or technologically challenging in vivo imaging platforms.